Method of treating gastrointestinal motility disorders

ABSTRACT

The present invention relates to a method for treating a mammal suffering from gastrointestinal motility disorders comprising administering certain thiadiazole and oxadiazole compounds that are herein disclosed.

CROSS-REFERENCE TO RELATED APPLICATION

The instant application is a continuation of Ser. No. 08/171,060 filedDec. 21, 1993, abandoned which is incorporated herein by reference.

BACKGROUND OF THE INVENTION

This invention provides a novel method for treating a mammal sufferingfrom gastrointestinal motility disorders.

The primary function of the gastrointestinal tract is the absorption ofingested nutrients. To achieve this primary function requires thattransit along the esophagus and gastrointestinal tract is at a rate thatallows for optimal digestion and absorption of water and electrolytes.Although the etiology and pathophysiology of esophageal andgastrointestinal motility disorders is incompletely understood, abnormalpatterns of gastrointestinal motility that result in stimulated motility(hypermotility) may cause many of the symptoms of disorders such asDiffuse Esophageal Spasm (an esophageal obstructive disordercharacterized by dysphagia), Achalasia (an obstructive disorder in whichthe lower esophageal sphincter fails to relax adequately resulting indysphagia), noncardiac chest pain and Functional Bowel Disorders such asthe Irritable Bowel Syndrome (IBS), non-ulcer dyspepsia, and idiopathicconstipation.

The afore mentioned esophageal and gastrointestinal disorders arecurrently incompletely understood, they are however thought to be theresult of abnormal motility (smooth muscle activity). Therefore, webelieve a rationale therapy would be to reduce the hypermotility andrestore normal patterns of esophageal and gastrointestinal motility. Inthe United States the only drugs approved for treating motilitydisorders are cisapride and metoclopramide, the latter a dopamine D2receptor antagonist that releases acetylcholine from the myentericplexus, consequently such as agent enhances motility which is notdesirable in treating hypermotility disorders. Presently, no efficacioustherapy exists for the treatment of esophageal and gastrointestinalhypermotility disorders. Observations with anticholinergics and smoothmuscle relaxants have been disappointing due to side effects such as drymouth and blurred vision for the anticholinergics and headaches withsmooth muscle relaxants such as nifedipine.

We have discovered a new class of selective muscarinic agents which havenot previously been considered for the use in treating motilitydisorders of the gastrointestinal tract.

SUMMARY OF THE INVENTION

The method of this invention comprises administering to a patientsuffering from gastrointestinal disorders an effective amount of acompound of the formula I ##STR1## wherein Z¹ is oxygen or sulphur;

R is hydrogen, halogen, amino, --NHCO--R², C₃₋₇ -cycloalkyl, C₄₋₁₀-(cycloalkylalkyl), --Z² --C₃₋₇ -cycloalkyl optionally substituted withC₁₋₆ -alkyl, --Z² --C₄₋₁₀ -(cycloalkylalkyl), --Z² --C₄₋₁₀-(cycloalkenylalkyl), --Z² --C₄₋₁₀ -(methylenecycloalkylalkyl),--NH--R², --NR² R³, --NH--OR², phenyl, phenoxy, benzoyl,benzyloxycarbonyl, tetrahydronaphtyl, indenyl, X, R², --Z² R², --SOR²,--SO₂ R², --Z² --R⁴ --Z³ --R³, --Z² --R⁴ --Z³ --R⁷ --Z⁴ --R³, --Z² --R⁴--CO--R³, --Z² --R⁴ --CO₂ --R³, --Z² --R⁴ --O₂ C--R³, --Z² --R⁴--CONH--R³, --Z² --R⁴ --NHCO--R³, --Z² --R⁴ --X, --Z² --R⁴ --Z³ --X,wherein Z², Z³ and Z⁴ independently are oxygen or sulphur, and R² and R³independently are straight or branched C₁₋₅ -alkyl, straight or branchedC₂₋₁₅ -alkenyl, straight or branched C₂₋₁₅ -alkynyl, each of which isoptionally substituted with halogen(s), --OH, --CN, --CF₃, --SH, --COOH,--NH--R², --NR² R³, C₁₋₆ -alkyl ester, one or two phenyl, phenoxy,benzoyl or benzyloxycarbonyl wherein each aromatic group is optionallysubstituted with one or two halogen, --CN, C₁₋₄ -alkyl or C₁₋₄ -alkoxy,and wherein R⁴ and R⁷ independently are straight or branched C₁₋₁₀-alkylene, straight or branched C₂₋₁₀ -alkenylene, straight or branchedC₂₋₁₀ -alkynylene, each of which is optionally substituted withhalogen(s), --OH, --CN, --CF₃, --SH, --COOH, --NH--R², --NR² R³, C₁₋₆-alkyl ester, one or two phenyl, phenoxy, benzoyl or benzyloxycarbonyl,and X is a 5 or 6 membered heterocyclic group containing one to four N,O or S atom(s) or a combination thereof, which heterocyclic group isoptionally substituted at carbon or nitrogen atom(s) with straight orbranched C₁₋₆ -alkyl, phenyl, benzyl or pyridine, or a carbon atom inthe heterocyclic group together with an oxygen atom form a carbonylgroup, or which heterocyclic group is optionally fused with a phenylgroup; and

R⁵ and R⁶ may be present at any position, including the point ofattachment of the thiadiazole or oxadiazole ring, and independently arehydrogen, straight or branched C₁₋₅ -alkyl, straight or branched C₂₋₅-alkenyl, straight or branched C₂₋₅ -alkynyl, straight or branched C₁₋₁₀-alkoxy, straight or branched C₁₋₅ -alkyl substituted with --OH, --OH,halogen, --NH₂ or carboxy;

R¹ is hydrogen, straight or branched C₁₋₅ -alkyl, straight or branchedC₂₋₅ -alkenyl or straight or branched C₂₋₅ -alkynyl; or apharmaceutically acceptable salt thereof.

Examples of such salts include inorganic and organic acid addition saltssuch as hydrochloride, hydrobromide, sulphate, phosphate, acetate,fumarate, maleate, citrate, lactate, tartrate, oxalate, or similarpharmaceutically acceptable inorganic or organic acid addition salts,and include the pharmaceutically acceptable salts listed in Journal ofPharmaceutical Science, 66, 2 (1977) which are hereby incorporated byreference.

Especially preferred salts include tartrate and hydrochloride.

As used herein, the term "patient" includes any mammal which couldbenefit from treatment of gastrointestinal disorders. The termparticularly refers to a human patient, but is not intended to be solimited.

The thiadiazole and oxadiazole compounds used in the presently claimedmethod have been disclosed and claimed in U.S. Pat. Nos. 5,041,455,5,043,345, European Patent Application 384288, PCT/DK91/00234 andPCT/DK91/00235. The thiadiazole and oxadiazole derivatives are known tobe cholinergic muscarinic agents useful in the treatment of presenileand senile dementia. The compounds are believed to be useful fortreating Alzheimer's disease, glaucoma, and painful conditions. Otherdisclosures suggest that thiadiazole compounds may be useful for thetreatment of illnesses whose clinical manifestations are due tocholinergic deficiency, (European Patent Application 307142). Suchillnesses include Huntington's chorea, tardive dyskinesia, hyperkinesia,mania, and Tourette Syndrome.

The compounds of the present invention are chemically and biologicallydifferent from that previously reported by Schiavone et al. (1988) andthe compounds inhibit small intestinal and colonic motility through acholinergic mechanism since the inhibition of motility is blocked byatropine (10 and 100 μg/kg i.v.). In addition these motility inhibitingcompounds have the desirable feature of having minimal effects onsalivation and heart rate.

In addition, the compounds of this method have been found to have afavourable profile of activity in a number of in vitro binding assays,designed to measure the degree of binding to neural receptors.

The compounds have IC₅₀ levels of less than 1 μM in the ³H-oxotremorine-M binding assay, indicating that the compounds havemuscarinic receptor affinity.

This profile of activity in in vitro receptor binding assays, like thatobserved in the motility tests, would indicate that the compounds areeffective in the treatment of gastrointestinal motility disorders.

Methods

Animals. Experiments were performed on fasted male ferret weighing0.8-1.5 kg). Anaesthesia was induced with urethane (1.5 g/kg i.p.), atracheal tube was inserted to provide a clear airway for spontaneousbreathing and the body temperature was maintained at 38° C. using ahomeothermic blanket. The left jugular vein was cannulated for thesubsequent administration of drugs and the carotid artery for thecontinual measurement of blood pressure and heart rate.

Motility Measurements. Following a laporatomy segments of jejunum andcolon were isolated from the remainder of the GI tract. In order torecord motility of predominantly the circular smooth muscle, asaline-filled cannula was inserted in an oral directed into the jejunumand colon.

Experimental Protocol. After an initial stabilization period,spontaneous motility was recorded for 30 min. then a bolus injection ofdrug was administered i.v. and flushed through the cannula with 1 ml ofphysiological saline (37° C.). After 10 min. a second dose wasinvestigated and changes in motility recorded for 10 min. If motilitydid not return to basal (pretreatment levels) more time was allowedbetween doses (up to 20 min.). All drugs were made up in physiologicalsaline and made fresh daily.

Data Analysis. Following the bolus injection of compound the duration ofloss of gastrointestinal motility was calculated. Most of the compoundswere tested at screening doses of 1, 3, 10 and 30 μg/kg i.v.

The affinity of the compounds for the muscarinic receptors wasdetermined using the non-selective agonist ligand, ³ H-oxotremorine-M.Birdsdall N. J. M., Hulme E. C., and Burgen A. S. V., "The Character ofMuscarinic Receptors in Different Regions of the Rat Brain", 207 Proc.Roy. Soc. 1 (London, Series B, 1980). The results of this assay aredescribed in Table I below. Each compound was tested to determine theaffinity of the compound for the muscarinic receptors using thefollowing procedure.

For each in vitro binding, male Sprague-Dawley (Harlan Sprague-Dawley,Indianapolis, Ind.) rats weighing from about 100 to about 150 grams eachwere sacrificed by decapitation. The brains were quickly removed and thecerebral cortex were dissected from the brain. The cerebral cortextissue was homogenized in 10 volumes of 0.32M sucrose and homogenizedfor about 10 minutes at about 1000×g. The supernatant was centrifuged atabout 12,000×g for about 10 minutes and the resulting pellet wasresuspended in 20 mM tris-Cl, pH 7.4. The resuspended pellet wascentrifuged again for about 10 minutes at about 50,000×g. The resultinghomogenate was preincubated for about 10 minutes at about 25° C. andcentrifuged again for about 10 minutes at about 50,000×g. The pellet wasresuspended at 1 gram of pellet per 3 ml of buffer and frozen at about-80° C. until used.

The inhibition of binding of ³ H-oxotremorine-M binding to muscarinicreceptors was determined by mixing the compound of the Example, 3 nM ³H-oxotremorine-M (about 87 Ci/mmoles, New England Nuclear, BostonMass.), and cerebral cortical membranes equivalent to about 10 mg wetweight, which is about 100 μg of cortical membrane protein, in about 1ml total volume of 20 nM tris-Cl buffer, pH 7.4, containing 1 mM MnCl₂.The aforementioned homogenates mixture was incubated for about 15minutes at about 25° C. and then the homogenates were filtered throughglass filters (Whatman, GF/C) with vacuum. The filters were washed 3times with about 2 ml of cold tris-Cl buffer, and placed inscintillation vials containing about 10 ml of scintillation fluid (ReadyProtein+, Beckman, Fullerton, Calif.). Radioactivity trapped on thefilters was determined by liquid scintillation spectrometry. Nonspecificbinding was determined using 1 μM atropine. The concentration ofcompound required to inhibit specific binding 50% (IC₅₀) was determinedusing standardized computer assisted calculations. DeLean, A. et al. Am.J. Physiol., 235, (1978).

Test results obtained by testing some compounds of the present inventionwill appear from the following Table 1:

                  TABLE 1                                                         ______________________________________                                                 Inhibition of                                                                             Jejunal motility                                                                         Colonic Motility                              Compound No.                                                                           .sup.3 H--Oxo (nM)                                                                        (μg/kg i.v.)                                                                          (μg/kg i.v.)                               ______________________________________                                        1        22                                                                   2        5.7                                                                  3        1.6                                                                  4        2.0                                                                  33       2.7         30         10                                            47       0.90                                                                 48       1.7                                                                  49       2.3                                                                  65       1.9                                                                  66       4.8                                                                  133      10.0        10         30                                            215      10.5                                                                 216      6.5                                                                  217      1.2                                                                  218      3.5                                                                  219      5.8                                                                  220      3.0                                                                  222      0.42                                                                 223      7.4                                                                  228      0.60                                                                 ______________________________________                                    

The compounds used in this method are effective over a wide dosagerange. For example, in the treatment of adult humans, dosages from about0.05 to about 100 mg, preferably from about 0.1 to about 100 mg, per daymay be used. A most preferable dosage is about 10 mg to about 70 mg perday. In choosing a regimen for patients suffering from gastrointestinalmotility disorders it may frequently be necessary to begin with a dosageof from about 30 to about 70 mg per day and when the condition is undercontrol to reduce the dosage as low as from about 1 to about 10 mg perday. The exact dosage will depend upon the mode of administration, formin which administered, the subject to be treated and the body weight ofthe subject to be treated, and the preference and experience of thephysician or veterinarian in charge.

The route of administration may be any route, which effectivelytransports the active compound to the appropriate or desired site ofaction, such as oral or parenteral e.g. rectal, transdermal,subcutaneous, intravenous, intramuscular or intranasal, the oral routebeing preferred.

Typical compositions include a compound of formula I or apharmaceutically acceptable acid addition salt thereof, associated witha pharmaceutically acceptable carrier. In making the compositions,conventional techniques for the preparation of pharmaceuticalcompositions may be used. For example, the active compound will usuallybe mixed with a carrier, or diluted by a carrier, or enclosed within acarrier which may be in the form of a ampoule, capsule, sachet, paper,or other container. When the carrier serves as a diluent, it may besolid, semi-solid, or liquid material which acts as a vehicle,excipient, or medium for the active compound. The active compound can beadsorbed on a granular solid container for example in a sachet. Someexamples of suitable carriers are water, salt solutions, alcohols,polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine,lactose, amylose, magnesium stearate, talc, silicic acid, fatty acidmonoglycerides and diglycerides, pentaerythritol fatty acid esters,hydroxymethylcellulose and polyvinylpyrrolidone.

The pharmaceutical preparations can be sterilized and mixed, if desired,with auxiliary agents, emulsifiers, salt for influencing osmoticpressure, buffers and/or coloring substances and the like, which do notdeleteriously react with the active compounds.

For parenteral application, particularly suitable are injectablesolutions or suspensions, preferably aqueous solutions with the activecompound dissolved in polyhydroxylated castor oil.

Tablets, dragees, or capsules having talc and/or a carbohydrate carrieror binder or the like are particularly suitable for oral application.Preferable carriers for tablets, dragees, or capsules include lactose,corn starch, and/or potato starch. A syrup or elixir can be used incases where a sweetened vehicle can be employed.

Generally, the compounds are dispensed in unit form comprising fromabout 1 to about 100 mg in a pharmaceutically acceptable carrier perunit dosage.

A typical tablet, appropriate for use in this method, may be prepared byconventional tabletting techniques and contains:

    ______________________________________                                        Active compound    5.0    mg                                                  Lactosum           67.8   mg Ph. Eur.                                         Avicel ®       31.4   mg                                                  Amberlite ®    1.0    mg                                                  Magnesii stearas   0.25   mg Ph. Eur.                                         ______________________________________                                    

The compounds used in this method may be prepared by commonly knownchemical methods. Most of the compounds may be prepared using themethods taught in in U.S. Pat. Nos. 5,041,455, 5,043,345, EuropeanPatent Application 384288, PCT/DK91/00234 and PCT/DK91/00235 which arehereby incorporated by reference. The following description is intendedto illustrate possible synthetic routes for the preparation of thecompounds utilized in this method.

The compounds may be prepared by

a) alkylating a compound of formula II ##STR2## wherein Z¹, R, R⁵ and R⁶have the meanings defined above with an alkyl halide and reducing thecompound thus formed with hydride ions to form a compound of formula I##STR3## wherein Z¹, R, R¹, R⁵ and R⁶ have the meanings defined above,or

b) oxidizing a compound of formula III ##STR4## wherein Z¹, R¹, R², R⁵and R⁶ have the meanings defined above by standard procedures to form acompound of formula IV ##STR5## and subsequent displacement of --SO₂--R² with an appropriate nucleophile to form a compound of formula I.

It is to be understood that the invention extends to each of thestereoisomeric forms of the compounds of formula I as well as theracemates.

The following examples are included to more specifically describe thepreparation of the compounds used in the method of this invention. Theexamples are not intended to limit the present invention in any way andshould not be so construed.

EXAMPLE 1

A. 3-(3-Chloro-1,2,5-thiadiazol-4-yl)pyridine

To a solution of sulfurmonochloride (2.4 ml, 30 mmol) inN,N-dimethylformamide (5 ml) was slowly addedalpha-aminoalpha(3-pyridyl)acetonitrile (Archive der Pharmazie 289 (4)(1956)) (1.70 g, 10 mmol). The reaction mixture was stirred at roomtemperature for 18 h. Water (20 ml) was added and the aqueous phase wasextracted with ether and the ether phase discharged. A 50% potassiumhydroxide solution was added to the aqueous phase to pH>9. The aqueousphase was extracted several times with ether and the ether phases weredried and evaporated. The residue was purified by column chromatography(SiO₂, eluent: ethyl acetate/methylene chloride (1:1)). The titlecompound was collected in 45% (880 mg) yield. M⁺ : 197.

B. 3-(3-Methoxy-1,2,5-thiadiazol-4-yl)pyridine

To a solution of sodium (460 mg, 20 mmol) in methanol (10 ml) was added3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (750 mg, 3.8 mmol). Themixturewas stirred at 50° C. for 1 h and evaporated. The residue wasdissolved in water and extracted with methylene chloride. The combinedorganic phases were dried and evaporated to give the title compound,whichcrystallized with petroleum ether in a 630 mg (86%) yield.

C. 3-(3-Methoxy-1,2,5-thiadiazol-4-yl)-1-methyl-pyridinium iodide

A mixture of methyl iodide (0.37 ml, 6 mmol) and3-(3-methoxy-1,2,5-thiadiazol-4-yl)pyridine (500 mg, 2.5 mmol) inacetone (10 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtration.Yield: 1.0g (100%).

D.1,2,5,6-Tetrahydro-3-(3-methoxy-1,2,5-thiadiazol-4-yl)-1-methylpyridineoxalate

Sodium borohydride (460 mg, 12 mmol) was added to a solution of3-(3-methoxy-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide (1.0 g, 3mmol) in ethanol (99.9%, 20 ml) and the reaction mixture was stirred atroom temperature for 1 h. After evaporation the residue was dissolved inwater and extracted with methylene chloride. The dried organic phaseswereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallizedas the oxalate salt from acetone. Yield: 390 mg. (M.p. 150°C.; M⁺ : 211; Compound 1).

EXAMPLE 2

A. 3-(3-Ethoxy-1,2,5-thiadiazol-4-yl)pyridine

To a solution of sodium (440 mg, 17 mmol) in ethanol (10 ml) was added3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (540 mg, 3.3 mmol). Themixturewas stirred at 40° C. for 10 h and evaporated. The residue wasdissolved in water and extracted with methylene chloride. The combinedorganic phases were dried and evaporated to yield 520 mg (76%) of thetitle compound.

B. 3-(3-Ethoxy-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (0.3 ml, 5 mmol) and3-(3-ethoxy-1,2,5-thiadiazol-4-yl)pyridine (520 mg, 2.5 mmol) in acetone(10 ml) was stirred at room temperature for 18 h. The title compoundprecipitated from the solution and was collected by filtration to yield0.72 g (83%).

C.3-(3-Ethoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (300 mg, 8 mmol) was added to a solution of3-(3-ethoxy-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide (0.72 g, 2mmol) in ethanol (99.9%, 20 ml) and the reaction mixture was stirred atroom temperature for 1 h. After evaporation the residue was dissolved inwater and extracted with methylene chloride. The dried organic phaseswereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallizedas the oxalate salt from acetone, and recrystallized frommethanol to yield190 mg. (M.p. 137° C.; M⁺ : 225; Compound 2).

EXAMPLE 3

A. 3-(3-Propoxy-1,2,5-thiadiazol-4-yl)pyridine

To a solution of sodium (440 mg, 17 mmol) in 1-propanol (10 ml) wasadded 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (650 mg, 3.3 mmol). Themixturewas stirred at 50° C. for 2 h and evaporated. The residue wasdissolved in water and extracted with methylene chloride. The combinedorganic phases were dried and evaporated to yield 700 mg (96%) of thetitle compound.

B. 3-(3-Propoxy-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (0.37 ml, 6 mmol) and3-(3-propoxy-1,2,5-thiadiazol-4-yl)pyridine (700 mg, 3.1 mmol) inacetone (10 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtrationto yield 0.98 g (88%).

C.1,2,5,6-Tetrahydro-1-methyl-3-(3-propoxy-1,2,5-thiadiazol-4-yl)-pyridineoxalate

Sodium borohydride (380 mg, 10 mmol) was added to a solution of3-(3-propoxy-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide (980 mg,2.7mmol) in ethanol (99.9%, 20 ml) and the reaction mixture was stirredat 0° C. for 1 h. After evaporation the residue was dissolved inwaterand extracted with ethyl acetate. The dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂eluent: ethylacetate/methanol (4:1)). The title compound wascrystallized as the oxalatesalt from acetone to yield 440 mg. (M.p. 148°C.; M⁺ : 239; Compound 3).

EXAMPLE 4

A. 3-(3-Butoxy-1,2,5-thiadiazol-4-yl)pyridine

To a solution of sodium (290 mg, 12.5 mmol) in n-butanol (10 ml) wasadded 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (490 mg, 2.5 mmol). Themixturewas stirred at 25° C. for 18 h and evaporated. The residue wasdissolved in water and extracted with methylene chloride. The combinedorganic phases were dried and evaporated to yield 580 mg (100%) of thetitle compound.

B. 3-(3-Butoxy-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (0.3 ml, 5 mmol) and3-(3-butoxy-1,2,5-thiadiazol-4-yl)pyridine (580 mg, 2.5 mmol) in acetone(5 ml) was stirred at room temperature for 18 h. The title compoundprecipitated from the solution and was collected by filtration to yield0.60 g (64%).

C.3-(3-Butoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (240 mg, 6.4 mmol) was added to a solution of3-(3-butoxy-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide (0.60 g,1.6 mmol) in ethanol (99.9%, 20 ml) and the reaction mixture was stirredat 0° C. for 1 h. After evaporation the residue was dissolved inwaterand extracted with ethyl acetate. The dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 280 mg. (M.p.158° C.; M⁺ :253; Compound 4).

EXAMPLE 5

A. 3-(3-Isopropoxy-1,2,5-thiadiazol-4-yl)pyridine

To a solution of sodium (290 mg, 12.5 mmol) in isopropanol (10 ml) wasadded 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (490 mg, 2.5 mmol). Themixture was stirred at 25° C. for 18 h and evaporated. The residue wasdissolved in water and extracted with ethyl acetate. The combinedorganic phases were dried and evaporated to yield 540 mg (98%) of thetitle compound.

B. 3-(3-Isopropoxy-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (0.3 ml, 5 mmol) and3-(3-isopropoxy-1,2,5-thiadiazol-4-yl)pyridine (540 mg, 2.4 mmol) inacetone (5 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtrationtoyield 0.68 g (77%).

C.1,2,5,6-Tetrahydro-3-(3-isopropoxy-1,2,5-thiadiazol-4-yl)-1-methylpyridineoxalate

Sodium borohydride (280 mg, 7.2 mmol) was added to a solution of3-(3-isopropoxy-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide (650mg, 1.8 mmol) in ethanol (99.9%, 20 ml) and the reaction mixture wasstirred at 0° C. for 1 h. After evaporation the residue was dissolved inwater and extracted with ethyl acetate. The dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallizedas the oxalate salt from acetone to yield 280 mg. (M.p. 164°C.; M⁺ : 239; Compound 5).

EXAMPLE 6

A. 3-(3-Pentyloxy-1,2,5-thiadiazol-4-yl)pyridine

To a solution of sodium (230 mg, 10 mmol) in 1-pentanol(20 ml) was added3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (490 mg, 2.5 mmol). Themixturewas stirred at 50° C. for 3 h and evaporated. The residue wasdissolved in water and extracted with methylene chloride. The combinedorganic phases were dried and evaporated to give the wanted compound.

B. 3-(3-Pentyloxy-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (0.3 ml, 5 mmol) and3-(3-pentyloxy-1,2,5-thiadiazol-4-yl)pyridine (620 mg, 2.5 mmol) inacetone (5 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtrationtoyield 0.81 g (84%).

C.1,2,5,6-Tetrahydro-1-methyl-3-(3-pentyloxy-1,2,5-thiadiazol-4-yl)-pyridineoxalate

Sodium borohydride (300 mg, 8 mmol) was added to a solution of3-(3-pentyloxy-3,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide (0.81 g,2mmol) in ethanol (99.9%, 20 ml) and the reaction mixture was stirred at0° C. for 1 h. After evaporation the residue was dissolved in waterandextracted with ether. The dried organic phases were evaporated and theresidue purified by column chromatography (SiO₂, eluent: ethylacetate/methanol (4:1)). The title compound was crystallized as theoxalate salt from acetone, and recrystallized from methanol to yield 220mg. (M.p. 150° C.; M⁺ : 267; Compound 6).

EXAMPLE 7

A. 3-(3-isobutoxy-1,2,5-thiadiazol-4-yl)pyridine

To a solution of sodium (230 mg, 10 mmol) in isobutanol (10 ml) wasadded 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (490 mg, 2.5 mmol). Themixturewas stirred at 50° C. for 3 h and evaporated. The residue wasdissolved in water and extracted with methylene chloride. The combinedorganic phases were dried and evaporated to give the wanted compound.

B. 3-(3-Isobutoxy-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (0.6 ml, 10 mmol) and3-(3-isobutoxy-1,2,5-thiadiazol-4-yl)pyridine (588 mg, 2.5 mmol) inacetone (5 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtrationtoyield 0.88 g (87%).

C.1,2,5,6-Tetrahydro-3-(3-isobutoxy-1,2,5-thiadiazol-4-yl)-1-methylpyridineoxalate

Sodium borohydride (160 mg, 4.3 mmol) was added to a solution of3-(3-isobutoxy-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide (0.82 g,2.2 mmol) in ethanol (99.9%, 20 ml) and the reaction mixture was stirredat 0° C. for 1 h. After evaporation the residue was dissolved in waterand extracted with ethyl acetate. The dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallizedas the oxalate salt from acetone to yield 400 mg. (M.p. 135°C.; M⁺ : 253; Compound 7).

EXAMPLE 8

A. 3-(3-Isopentyloxy-1,2,5-thiadiazol-4-yl)pyridine

To a solution of sodium (230 mg, 10 mmol) in isopentanol (20 ml) wasadded 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (490 mg, 2.5 mmol). Themixturewas stirred at 50° C. for 2 h and evaporated. The residue wasdissolved in water and extracted with ether. The combined organic phaseswere dried and evaporated to give the wanted compound.

B. 3-(3-Isopentyloxy-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (0.5 ml, 10 mmol) and3-(3-isopentyloxy-1,2,5-thiadiazol-4-yl)pyridine (622 mg, 2.5 mmol) inacetone (5 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtrationtoyield 0.78 g (81%).

C.1,2,5,6-Tetrahydro-3-(3-isopentyloxy-1,2,5-thiadiazol-4-yl)-1-methylpyridineoxalate

Sodium borohydride (150 mg, 4 mmol) was added to a solution of3-(3-isopentyloxy-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide (780mg, 2 mmol) in ethanol (99.9%, 20 ml) and the reaction mixture wasstirredat 0° C. for 1 h. After evaporation the residue was dissolved inwater and extracted with ethyl acetate. The dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallizedas the oxalate salt from acetone to yield 350 mg. (M.p. 152°C.; M⁺ : 267; Compound 8).

EXAMPLE 9

A. 3-(3-Hexyloxy-1,2,5-thiadiazol-4-yl)pyridine

To a solution of sodium (230 mg, 10 mmol) in 1-hexanol (15 ml) was added3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (490 mg, 2.5 mmol). Themixturewas stirred at 50° C. for 2 h and evaporated. The residue wasdissolved in water and extracted with ether. The combined organic phaseswere dried and evaporated to give the wanted compound.

B. 3-(3-Hexyloxy-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (0.5 ml, 7.5 mmol) and3-(3-hexyloxy-1,2,5-thiadiazol-4-yl)pyridine (658 mg, 2.5 mmol) inacetone(5 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtrationto yield 0.81 g (80%).

C.3-(3-Hexyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (230 mg, 6 mmol) was added to a solution of3-(3-hexyloxy-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide (810 mg,2 mmol) in ethanol (99.9%, 20 ml) and the reaction mixture was stirredat room temperature for 1 h. After evaporation the residue was dissolvedin water and extracted with ethyl acetate. The dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallizedas the oxalate salt from acetone to yield 350 mg. (M.p. 148°C.; M⁺ : 281; Compound 9).

EXAMPLE 10

A. 3-(3-Benzyloxy-1,2,5-thiadiazol-4-yl)pyridine

To a solution of sodium (490 mg, 2.5 mmol) in benzyl alcohol (15 ml) wasadded 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (490 mg, 2.5 mmol). Themixture was stirred at 50° C. for 2 h and evaporated. The residue wasdissolved in water and extracted with ether. The combined organic phaseswere dried and evaporated to give the wanted compound.

B. 3-(3-Benzyloxy-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (0.5 ml, 7.5 mmol) and3-(3-benzyloxy-1,2,5-thiadiazol-4-yl)pyridine (673 mg, 2.5 mmol) inacetone (5 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtrationtoyield 0.75 g (73%).

C.3-(3-Benzyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (230 mg, 6 mmol) was added to a solution of3-(3-benzyloxy-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide (750 mg,1.8 mmol) in ethanol (99.9%, 20 ml) and the reaction mixture was stirredat 0° C. for 1 h. After evaporation the residue was dissolved in waterand extracted with ethyl acetate. The dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallizedas the oxalate salt from acetone to yield 340 mg. (M.p. 149°C.; M⁺ : 287; Compound 10).

EXAMPLE 11

A. 3-(3-(3-Butenyloxy)-1,2,5-thiadiazol-4-yl)pyridine

To a solution of 3-buten-1-ol (540 mg, 7.5 mmol) and sodium hydride (180mg, 7.5 mmol) in dry tetrahydrofuran was added a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (490 mg, 2.5 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 1 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to yield 650 mg of the titlecompound.

B. 3-(3-(3-Butenyloxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (0.5 ml, 7.5 mmol) and3-(3-(3-butenyloxy)-1,2,5-thiadiazol-4-yl)pyridine (583 mg, 2.5 mmol) inacetone (5 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtrationtoyield 890 mg (96%).

C.3-(3-(3-Butenyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (210 mg, 5.5 mmol) was added to a solution of3-(3-(3-butenyloxy-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide(1.03 g, 2.8 mmol) in ethanol (99.9%, 20 ml) and the reaction mixturewas stirred at 0° C. for 1 h. After evaporation the residue wasdissolved in water and extracted with ethyl acetate. The dried organicphases were evaporated and the residue purified by column chromatography(SiO₂, eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 380 mg. (M.p.141° C.; M⁺ : 251; Compound 11).

EXAMPLE 12

A. 3-(3-(2-Butynyloxy)-1,2,5-thiadiazol-4-yl)pyridine

To a solution of 2-butyn-1-ol (530 mg, 7.5 mmol) and sodiumhydride (180mg,7.5 mmol) in dry tetrahydrofuran was added a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (490 mg, 2.5 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 2 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to give the title compound.

B. 3-(3-(2-Butynyloxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (0.5 ml, 7.5 mmol) and3-(3-(2-butynyloxy)-1,2,5-thiadiazol-4-yl)pyridine (578 mg, 2.5 mmol) inacetone (5 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtrationtoyield 0.88 g (95%).

C.3-(3-(2-Butynyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (180 mg, 4.7 mmol) was added to a solution of3-(3-(2-butynyloxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide(0.88g, 2.35 mmol) in ethanol (99.9%, 20 ml) and the reaction mixturewas stirred at 0° C. for 1 h. After evaporation the residue wasdissolved in water and extracted with ethyl acetate. The dried organicphases were evaporated and the residue purified by column chromatography(SiO₂, eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone, and recrystallized inmethanol to yield 140 mg. (M.p. 158° C.; M⁺ : 249; Compound 12).

EXAMPLE 13

A. 3-(3-Propargyloxy-1,2,5-thiadiazol-4-yl)pyridine

To a solution of propargyl alcohol (420 mg, 7.5 mmol) and sodium hydride(180 mg, 7.5 mmol) in dry tetrahydrofuran was added a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (490 mg, 2.5 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 2 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to yield 530 mg (98%) of the titlecompound.

B. 3-(3-Propargyloxy-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (0.45 ml, 7.2 mmol) and3-(3-propargyloxy-1,2,5-thiadiazol-4-yl)pyridine (430 mg, 2.4 mmol) inacetone (5 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtrationtoyield 0.58 g (67%).

C.1,2,5,6-Tetrahydro-1-methyl-3-(3-propargyloxy-1,2,5-thiadiazol-4-yl)pyridineoxalate

Sodium borohydride (230 mg, 6 mmol) was added to a solution of3-(3-propargyloxy-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide (0.68g, 1.9 mmol) in ethanol (99.9%, 20 ml) and the reaction mixture wasstirred at 0° C. for 1 h. After evaporation the residue was dissolved inwater and extracted with ethyl acetate. The dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 200 mg. (M.p.155° C.; M⁺ : 235; Compound 13).

EXAMPLE 14

A. 3-(3-Cyclopropylmethoxy-1,2,5-thiadiazol-4-yl)pyridine

To a solution of cyclopropylcarbinol (360 mg, 5 mmol) and sodium hydride(110 mg, 5 mmol) in dry tetrahydrofuran was added a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (490 mg, 2.5 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 3 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to yield 400 mg (69%) of the titlecompound.

B. 3-(3-Cyclopropylmethoxy-1,2,5-thiadiazol-4-yl)-1-methylpyridiniumiodide

A mixture of methyl iodide (0.25 ml, 4 mmol) and3-(3-cyclopropylmethoxy-1,2,5-thiadiazol-4-yl)pyridine (400 mg, 1.7mmol) in acetone (5 ml) was stirred at room temperature for 36 h. Thetitle compound precipitated from the solution and was collected byfiltration toyield 0.41 g (65%).

C.3-(3-Cyclopropylmethoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (170 mg, 4.4 mmol) was added to a solution of3-(3-cyclopropylmethoxy-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide(410 mg, 1.1 mmol) in ethanol (99.9%, 20 ml) and the reaction mixturewas stirred at 0° C. for 1 h. After evaporation the residue wasdissolved in water and extracted with ethyl acetate. The dried organicphases were evaporated and the residue purified by column chromatography(SiO₂, eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 130 mg. (M.p.153° C.; M⁺ : 251; Compound 14).

EXAMPLE 15

A. 3-(3-Chloro-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide

A solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (1.98 g, 10mmol) and methyl iodide (4.25 g, 30 mmol) in acetone (10 ml) was stirredat roomtemperature for 16 h. The precipitate was collected by filtrationto yield 3.40 g (100%) of the title compound.

B.3-(3-Chloro-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

To a suspension of sodium borohydride (330 mg, 8.6 mmol) in ethanol (20ml)was added 3-(3-chloro-1,2,5-thiadiazol-4-yl)-1-methylpyridiniumiodide (1.46 g, 4.3 mmol) at 0° C. The reaction mixture was stirred for1 h at 0° C. Water was added and the mixture was extracted withethylacetate. After drying, the ethyl acetate phase was evaporated andthe residue purified by column chromatography (eluent: ethylacetate:methanol (4:1)). Yield: 880 mg (95%). Crystallization withoxalic acid from acetonegave the title compound. (M.p. 124° C.; M⁺ : 215and 217; Compound 16).

C.1,2,5,6-Tetrahydro-3-(3-methoxyethoxy-1,2,5-thiadiazol-4-yl)-1-methylpyridineoxalate

To a solution of sodium (120 mg, 5 mmol) in 2-methoxyethanol (10 ml) wasadded3-(3-chloro-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate (310 mg, 1 mmol). The mixture was stirred at 50° C. for 18 h andevaporated. The residue was dissolved in water and extracted with ethylacetate. The combined organic phases were dried and evaporated. Thetitle compound was crystallized as the oxalate salt from acetone toyield 270 mg. (M.p. 152.1° C.; M⁺ : 253; Compound 15).

D. 3-(3-Chloro-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydropyridinehydrochloride

To a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine(670 mg, 3.1 mmol) in 1,2-dichloroethane (20 ml) was added a solution of1-chloroethyl-chloroformate (440 mg, 3.1 mmol) in 1,2-dichloroethane at0° C. The reaction mixture was heated to 40° C. for 2 h and evaporated.The residue was dissolved in methanol and heated to reflux for1 h. Aftercooling to room temperature the precipitate was collected by filtrationto yield 320 mg (41%). (M.p. 224° C.; M⁺ : 201 and 203; Compound 17).

E. 3-(3-Butoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydropyridine oxalate

To a solution of sodium (150 mg, 6.5 mmol) in 1-butanol (15 ml) wasadded 3-(3-chloro-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydropyridinehydrochloride (240 mg, 1 mmol). The reaction mixture was stirred at 50°C. for 1 h. After evaporation the residue was dissolved in water andextracted with ethyl acetate. The ethyl acetate phase was dried andevaporated to give an oil (200 mg). Crystallization as the oxalate saltfrom acetone gave the title compound. Yield: 170 mg (52%). (M.p.173°-174° C.; M⁺ : 239; Compound 18).

EXAMPLE 16

A. 3-(3-Chloro-1,2,5-thiadiazol-4-yl)-1-ethylpyridiniumiodide

A solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (1.13 g, 5.7mmol)and ethyl iodide (22.65 g, 17 mmol) in acetone (15 ml) was stirredat 40° C. for 16 h. The precipitate was collected by filtrationgivingthe title compound. Yield: 510 mg (26%).

B. 3-(3-Chloro-1,2,5-thiadiazol-4-yl)-1-ethyl-1,2,5,6-tetrahydropyridineoxalate

To a suspension of sodium borohydride (170 mg, 4.5 mmol) in ethanol (10ml)was added 3-(3-chloro-1,2,5-thiadiazol-4-yl)-1-ethylpyridinium iodide(510 mg, 1.5 mmol) at 0° C. The mixture was stirred for 1 h at 0°C.Water was added and the mixture was extracted with ethyl acetate. Afterdrying, the ethyl acetate phase was evaporated and the residue purifiedbycolumn chromatography (eluent: ethyl acetate/methanol (4:1)).Crystallization with oxalic acid from acetone gave the title compound toyield 70 mg. (M.p. 143° C.; M⁺ : 229 and 231; Compound 19).

EXAMPLE 17

A. 3-(3-Ethoxy-1,2,5-thiadiazol-4-yl)-1-ethylpyridinium iodide

A solution of 3-(3-ethoxy-1,2,5-thiadiazol-4-yl)pyridine (0.90 g, 4.3mmol)and ethyl iodide (2.03 g, 13 mmol) in acetone (4 ml) was stirred at40° C. for 16 h. The precipitate was collected by filtration givingthetitle compound to yield 1.34 g (86%).

B. 3-(3-Ethoxy-1,2,5-thiadiazol-4-yl)-1-ethyl-1,2,5,6-tetrahydropyridineoxalate

To a suspension of sodium borohydride (410 mg, 10.8 mmol) in ethanol (10ml) was added 3-(3-ethoxy-1,2,5-thiadiazol-4-yl)-1-ethylpyridiniumiodide (1.32 g, 3.6 mmol) at 0° C. The mixture was stirred for 1 h at 0°C. Water was added and the mixture was extracted with ethyl acetate.After drying, the ethyl acetate phase was evaporated and the residuepurified by column chromatography (eluent: ethyl acetate/methanol(4:1)). Crystallization with oxalic acid from acetone gave a yield of0.49g of the title compound. (M.p. 120°-122° C.; M⁺ : 239; Compound 20).

The following compounds were prepared in exactly the same manner:

3-(3-Hexylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-ethylpyridineoxalate from 3-(3-Hexylthio-1,2,5-thiadiazol-4-yl)pyridine. M.p.134°-135° C. Compound 209.

3-(3-Ethylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-ethylpyridineoxalate from 3-(3-ethylthio-1,2,5-thiadiazol-4-yl)pyridine. M.p.151°-152° C. Compound 210.

3-(3-Hexyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-ethylpyridineoxalate from 3-(3-hexyloxy-1,2,5-thiadiazol-4-yl)pyridine. M.p.138°-139° C. Compound 211.

EXAMPLE 183-(3-Heptyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

To a solution of sodium (120 mg, 5 mmol) in 1-heptanol (10 ml) was added3-(3-chloro-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate (310 mg, 1 mmol). The reaction mixture was stirred at 50° C. for18 h. After evaporation the residue was dissolved in water and extractedwith ethyl acetate. The ethyl acetate phase was dried and evaporated togive an oil. Crystallization as the oxalate salt from acetone gave thetitle compound. Yield: 270 mg (70%). (M.p. 152° C.; M⁺ : 295; Compound21).

EXAMPLE 19

A. 3-(3-(3-Pentynyloxy)-1,2,5-thiadiazol-4-yl)pyridine

To a solution of 3-pentyn-1-ol (750 mg, 9 mmol) and sodium hydride (310mg,9 mmol) in dry tetrahydrofuran was added a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (590 mg, 3 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 1 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to give the title compound.

B. 3-(3-(3-Pentynyloxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (0.6 ml, 9 mmol) and3-(3-(3-pentynyloxy)-1,2,5-thiadiazol-4-yl)pyridine (3 mmol) in acetone(10 ml) was stirred at room temperature for 18 h. The title compoundprecipitated from the solution and was collected by filtration to yield0.68 g (59%).

C.3-(3-(3-Pentynyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (150 mg, 4 mmol) was added to a solution of3-(3-(3-pentynyloxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide(0.68 g, 1.7 mmol) in ethanol (99.9%, 15 ml) and the reaction mixturewas stirred at -10° C. for 1 h. After evaporation the residue wasdissolved in water and extracted with ethyl acetate. The dried organicphases were evaporated and the residue purified by column chromatography(SiO₂, eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 240 mg. (M.p.166°-167° C.; M⁺ : 263; Compound 22).

EXAMPLE 20

A. 3-(3-(4-Pentenyloxy)-1,2,5-thiadiazol-4-yl)pyridine

To a solution of 4-penten-1-ol (640 mg, 7.5 mmol) and sodium hydride(260 mg, 7.5 mmol) in dry tetrahydrofuran was added a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (490 mg, 2.5 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 1 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to give the title compound.

B. 3-(3-(4-Pentenyloxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (0.5 ml, 7.5 mmol) and3-(3-(4-pentenyloxy)-1,2,5-thiadiazol-4-yl)pyridine (2.5 mmol) inacetone (10 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtrationto yield 0.67 g (69%).

C.3-(3-(4-Pentenyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (150 mg, 4 mmol) was added to a solution of3-(3-(4-pentenyloxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide(0.67 g, 1.7 mmol) in ethanol (99.9%, 15 ml) and the reaction mixturewas stirred at -10° C. for 1 h. After evaporation the residue wasdissolved in water and extracted with ethyl acetate. The dried organicphases were evaporated and the residue purified by column chromatography(SiO₂, eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 150 mg. (M.p.141°-142° C.; M⁺ : 265; Compound 23).

EXAMPLE 21

A. 3-(3-(2-Propenyloxy)-1,2,5-thiadiazol-4-yl)pyridine

To a solution of allyl alcohol (650 mg, 9 mmol) and sodium hydride (310mg,9 mmol) in dry tetrahydrofuran was added a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (590 mg, 3 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 1 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to give the title compound.

B. 3-(3-(2-Propenyloxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (0.4 ml, 6 mmol) and3-(3-(2-propenyloxy)-1,2,5-thiadiazol-4-yl)pyridine (3 mmol) in acetone(5ml) was stirred at room temperature for 18 h. The title compoundprecipitated from the solution and was collected by filtration to give0.96 g (88%).

C.3-(3-(2-Propenyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (210 mg, 5.5 mmol) was added to a solution of3-(3-(2-propenyloxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide(0.96 g, 2.6 mmol) in ethanol (99.9%, 25 ml) and the reaction mixturewas stirred at -10° C. for 1 h. After evaporation the residue wasdissolved in water and extracted with ethyl acetate. The dried organicphases were evaporated and the residue purified by column chromatography(SiO₂, eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 270 mg. (M.p.136°-137° C.; M⁺ : 237; Compound 24).

EXAMPLE 22

A. 3-(3-Octyloxy-1,2,5-thiadiazol-4-yl)pyridine

To a solution of sodium (350 mg, 15 mmol) in 1-octanol (10 ml) was added3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (590 mg, 3 mmol). The mixturewas stirred at 50° C. for 1 h and evaporated. The residue was dissolvedin water and extracted with methylene chloride. The combined organicphases were dried and evaporated to give the title compound.

B. 3-(3-Octyloxy-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (1 ml, 15 mmol) and3-(3-octyloxy-1,2,5-thiadiazol-4-yl)pyridine (3 mmol) in acetone (5 ml)was stirred at room temperature for 18 h. The title compoundprecipitated from the solution and was collected by filtration to yield0.81 g (62%).

C.3-(3-Octyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (210 mg, 5.6 mmol) was added to a solution of3-(3-octyloxy-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide (0.81 g,1.87 mmol) in ethanol (99.9%, 10 ml) and the reaction mixture wasstirred at -10° C. for 1 h. After evaporation the residue was dissolvedin water and extracted with ethyl acetate. The dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallizedas the oxalate salt from acetone to yield 330 mg. (M.p.144°-145° C.; M⁺ : 309; Compound 25).

EXAMPLE 23

A. 3-(3-(3-Hexynyloxy)-1,2,5-thiadiazol-4-yl)pyridine

To a solution of 3-hexyn-1-ol (880 mg, 9 mmol) and sodium hydride (310mg, 9 mmol) in dry tetrahydrofuran was added a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (590 mg, 3 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 1 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to give the title compound.

B. 3-(3-(3-Hexynyloxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (1 ml, 15 mmol) and3-(3-(3-hexynyloxy)-1,2,5-thiadiazol-4-yl)pyridine (3 mmol) in acetone(5 ml) was stirred at room temperature for 18 h. The title compoundprecipitated from the solution and was collected by filtration to yield0.85 g (71%).

C.3-(3-(3-Hexynyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (190 mg, 5 mmol) was added to a solution of3-(3-(3-hexynyloxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide(0.85g, 2.1 mmol) in ethanol (99.9%, 10 ml) and the reaction mixture wasstirredat -10° C. for 1 h. After evaporation the residue was dissolvedin water and extracted with ethyl acetate. The dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallizedas the oxalate salt from acetone to yield 350 mg. (M.p.174°-175° C.; M⁺ : 277; Compound 26).

EXAMPLE 24

A. 3-(3-(3-Methyl-2-butenyloxy)-1,2,5-thiadiazol-4-yl)pyridine

To a solution of 3-methyl-2-buten-1-ol (780 mg, 9 mmol) andsodiumhydride (310 mg, 9 mmol) in dry tetrahydrofuran was added asolution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (590 mg, 3 mmol)in dry tetrahydrofuran. The reaction mixture was stirred at roomtemperature for 0.3 h. Water was added and the mixture was extractedwith ether. The etherphase was dried and evaporated to give the titlecompound.

B.3-(3-(3-Methyl-2-butenyloxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridiniumiodide

A mixture of methyl iodide (1 ml, 15 mmol) and3-(3-(3-methyl-2-butenyloxy)-1,2,5-thiadiazol-4-yl)pyridine (3 mmol) inacetone (3 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtrationtoyield 0.92 g (79%).

C.3-(3-(3-Methyl-2-butenyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (220 mg, 6 mmol) was added to a solution of3-(3-(3-methyl-2-butenyloxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridiniumiodide (0.92 g, 2.3 mmol) in ethanol (99.9%, 15 ml) and the reactionmixture was stirred at -10° C. for 0.5 h. After evaporation the residuewas dissolved in water and extracted with ethyl acetate. Thedriedorganic phases were evaporated and the residue purified by columnchromatography (SiO₂, eluent: ethyl acetate/methanol (4:1)). The titlecompound was crystallized as the oxalate salt from acetone to yield 380mg. (M.p. 150°-151° C.; M⁺ : 265; Compound 27).

EXAMPLE 25

A. 3-(3-(3-Butenyl-2-oxy)-1,2,5-thiadiazol-4-yl)pyridine

To a solution of 3-buten-2-ol (650 mg, 9 mmol) and sodium hydride (310mg, 9 mmol) in dry tetrahydrofuran was added a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (590 mg, 3 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 18 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to give the title compound.

B. 3-(3-(3-Butenyl-2-oxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridiniumiodide

A mixture of methyl iodide (1 ml, 15 mmol) and3-(3-(3-butenyl-2-oxy)-1,2,5-thiadiazol-4-yl)pyridine (3 mmol) inacetone (3 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtrationto yield 0.73 g (65%).

C.3-(3-(3-Butenyl-2-oxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (190 mg, 5 mmol) was added to a solution of3-(3-(3-butenyl-2-oxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide(0.73 g, 1.9 mmol) in ethanol (99.9%, 15 ml) and the reaction mixturewas stirred at -10° C. for 0.5 h. After evaporation the residue wasdissolved in water and extracted with ethyl acetate. The dried organicphases were evaporated and the residue purified by column chromatography(SiO₂, eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 270 mg. (M.p.134°-135° C.; M⁺ : 251; Compound 28).

EXAMPLE 26

A. 3-(3-(4-Hexenyloxy)-1,2,5-thiadiazol-4-yl)pyridine

To a solution of 4-hexen-1-ol (900 mg, 9 mmol) and sodium hydride (310mg, 9 mmol) in dry tetrahydrofuran was added a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (590 mg, 3 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 1 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to give the title compound.

B. 3-(3-(4-Hexenyloxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (1 ml, 15 mmol) and3-(3-(4-hexenyloxy)-1,2,5-thiadiazol-4-yl)pyridine (3 mmol) in acetone(5 ml) was stirred at room temperature for 18 h. The title compoundprecipitated from the solution and was collected by filtration to yield0.54 g (45%).

C.3-(3-(4-Hexenyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (150 mg, 4 mmol) was added to a solution of3-(3-(4-hexenyloxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide(0.54g, 1.3 mmol) in ethanol (99.9%, 15 ml) and the reaction mixture wasstirredat -10° C. for 0.5 h. After evaporation the residue was dissolvedinwater and extracted with ethyl acetate. The dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallizedas the oxalate salt from acetone to yield 190 mg. (M.p.151°-152° C.; M⁺ : 279; Compound 29).

EXAMPLE 27

A. trans-3-(3-(3-Hexenyloxy)-1,2,5-thiadiazol-4-yl)pyridine

To a solution of trans-3-hexen-1-ol (900 mg, 9 mmol) and sodium hydride(310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl) pyridine (590 mg, 3 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 1 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to give the title compound.

B. trans-3-(3-(3-Hexenyloxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridiniumiodide

A mixture of methyl iodide (1 ml, 15 mmol) andtrans-3-(3-(3-hexenyloxy)-1,2,5-thiadiazol-4-yl)pyridine (3 mmol) inacetone (5 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtrationtoyield 0.90 g (75%).

C.trans-3-(3-(3-Hexenyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (190 mg, 5 mmol) was added to a solution oftrans-3-(3-(3-hexenyloxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridiniumiodide(0.90 g, 2.2 mmol) in ethanol (99.9%, 15 ml) and the reactionmixture was stirred at -10° C. for 0.5 h. After evaporation the residuewas dissolved in water and extracted with ethyl acetate. The driedorganic phases were evaporated and the residue purified by columnchromatography (SiO₂, eluent: ethyl acetate/methanol (4:1)). The titlecompound was crystallized as the oxalate salt from acetone to yield 420mg. (M.p. 163°-164° C.; M⁺ : 279; Compound 30).

EXAMPLE 28

A. cis-3-(3-(2-Pentenyloxy)-1,2,5-thiadiazol-4-yl)-pyridine

To a solution of cis-2-penten-1-ol (780 mg, 9 mmol) and sodium hydride(310mg, 9 mmol) in dry tetrahydrofuran was added a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (590 mg, 3 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 1 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to give the title compound.

B. cis-3-(3-(2-Pentenyloxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridiniumiodide

A mixture of methyl iodide (1 ml, 15 mmol) andcis-3-(3-(2-pentenyloxy)-1,2,5-thiadiazol-4-yl)pyridine (3 mmol) inacetone (5 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtrationtoyield 0.53 g (46%).

C.cis-3-(3-(2-Pentenyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahyro-1-methylpyridineoxalate

Sodium borohydride (150 mg, 4 mmol) was added to a solution ofcis-3-(3-(2-pentenyloxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridiniumiodide (0.53 g, 1.3 mmol) in ethanol (99.9%, 15 ml) and the reactionmixture was stirred at -10° C. for 0.5 h. After evaporation the residuewas dissolved in water and extracted with ethyl acetate. The driedorganic phases were evaporated and the residue purified by columnchromatography (SiO₂, eluent: ethyl acetate/methanol (4:1)). The titlecompound was crystallized as the oxalate salt from acetone to yield 210mg. (M.p. 143°-144° C.; M⁺ : 265; Compound 31).

EXAMPLE 29

A. cis-3-(3-(2-Hexenyloxy)-1,2,5-thiadiazol-4-yl)pyridine

To a solution of cis-2-hexen-1-ol (900 mg, 9 mmol) and sodium hydride(310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl) pyridine (590 mg, 3 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 1 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to give the title compound.

B. cis-3-(3-(2-Hexenyloxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridiniumiodide

A mixture of methyl iodide (0.5 ml, 7.5 mmol) andcis-3-(3-(2-hexenyloxy)-1,2,5-thiadiazol-4-yl)pyridine (3 mmol) inacetone(4 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtration.

C.cis-3-(3-(2-Hexenyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (150 mg, 4 mmol) was added to a solution ofcis-3-(3-(2-hexenyloxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide(0.6 g, 1 mmol) in ethanol (99.9%, 20 ml) and the reaction mixture wasstirred at -10° C. for 0.5 h. After evaporation the residue wasdissolved in water and extracted with ethyl acetate. The dried organicphases were evaporated and the residue purified by column chromatography(SiO₂, eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 150 mg. (M.p.122°-123° C.; M⁺ : 279; Compound 32).

EXAMPLE 30

A. 3-(3-(5-Hexenyloxy)-1,2,5-thiadiazol-4-yl)pyridine

To a solution of 5-hexen-1-ol (900 mg, 9 mmol) and sodium hydride (310mg, 9 mmol) in dry tetrahydrofuran was added a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (590 mg, 3 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 1 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to give the title compound.

B. 3-(3-(5-Hexenyloxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (0.5 ml, 7.5 mmol) and3-(3-(5-hexenyloxy)-1,2,5-thiadiazol-4-yl)pyridine (3 mmol) in acetone(5 ml) was stirred at room temperature for 18 h. The title compoundprecipitated from the solution and was collected by filtration to yield0.75 g (62%).

C.3-(3-(5-Hexenyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (150 mg, 4 mmol) was added to a solution of3-(3-(5-hexenyloxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide(0.75g, 1.8 mmol) in ethanol (99.9%, 20 ml) and the reaction mixture wasstirredat -10° C. for 0.5 h. After evaporation the residue was dissolvedinwater and extracted with ethyl acetate. The dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/ methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 250 mg. (M.p.137°-138° C.; M⁺ : 279; Compound 33).

EXAMPLE 31

A. cis-3-(3-(3-Hexenyloxy)-1,2,5-thiadiazol-4-yl)pyridine

To a solution of cis-3-hexen-1-ol (900 mg, 9 mmol) and sodium hydride(310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl) pyridine (590 mg, 3 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 1 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to give the title compound.

B. cis-3-(3-(3-Hexenyloxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridiniumiodide

A mixture of methyl iodide (0,5 ml, 7.5 mmol) andcis-3-(3-(3-hexenyloxy)-1,2,5-thiadiazol-4-yl)pyridine (3 mmol) inacetone(5 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtrationto yield 0.9 g (46%).

C.cis-3-(3-(3-Hexenyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (230 mg, 6 mmol) was added to a solution ofcis-3-(3-(3-hexenyloxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide(0.90 g, 2.2 mmol) in ethanol (99.9%, 15 ml) and the reaction mixturewas stirred at -10° C. for 0.5 h. After evaporation the residue wasdissolved in water and extracted with ethyl acetate. The dried organicphases were evaporated and the residue purified by column chromatography(SiO₂, eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 300 mg. (M.p.149°-150° C.; M⁺ : 279; Compound 34).

EXAMPLE 32

A. trans-3-(3-(2-Hexenyloxy)-1,2,5-thiadiazol-4-yl)pyridine

To a solution of trans-2-hexen-1-ol (900 mg, 9 mmol) and sodium hydride(310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl) pyridine (590 mg, 3 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 1 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to give the title compound.

B. trans-3-(3-(2-Hexenyloxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridiniumiodide

A mixture of methyl iodide (0.5 ml, 7.5 mmol) andtrans-3-(3-(2-hexenyloxy)-1,2,5-thiadiazol-4-yl)pyridine (3 mmol) inacetone (5 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtrationtoyield 1.09 g (90%).

C.trans-3-(3-(2-Hexenyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (270 mg, 4 mmol) was added to a solution oftrans-3-(3-(2-hexenyloxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridiniumiodide(1.09 g, 2.7 mmol) in ethanol (99.9%, 20 ml) and the reactionmixture was stirred at -10° C. for 0.5 h. After evaporation the residuewas dissolved in water and extracted with ethyl acetate. The driedorganic phases were evaporated and the residue purified by columnchromatography (SiO₂, eluent: ethyl acetate/methanol (4:1)). The titlecompound was crystallized as the oxalate salt from acetone to yield 400mg. (M.p. 130°-131° C.; M⁺ : 279; Compound 35).

EXAMPLE 33

A. 3-(1,2,5-Thiadiazol-3-yl)pyridine

To a solution of 1-butanethiol (2.7 g, 30 mmol) and sodium hydride (1.2g, 30 mmol) in dry tetrahydrofuran was added a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (1.2 g, 6 mmol) in drytetrahydrofuran. The reaction mixture was stirred at -10° C. for 0.5 h.Water was added and the mixture was extracted with ether. The etherphasewas dried and evaporated. The residue was purified by columnchromatography (SiO₂, eluent: ethyl acetate/methylene chloride (1:1))togive the title compound.

B. 3-(1,2,5-Thiadiazol-3-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (1 ml, 15 mmol) and3-(1,2,5-thiadiazol-3-yl)pyridine (6 mmol) in acetone (5 ml) was stirredat room temperature for 18 h. The title compound precipitated from thesolution and was collected by filtration to yield 1.2 g (74%).

C. 3-(1,2,5-Thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine oxalate

Sodium borohydride (380 mg, 10 mmol) was added to a solution of3-(1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide (1.2 g, 4.4 mmol) inethanol (99.9%, 20 ml) and the reaction mixture was stirred at -10°C.for 0.5 h. After evaporation the residue was dissolved in water andextracted with ethyl acetate. The dried organic phases were evaporatedandthe residue purified by column chromatography (SiO₂, eluent: ethylacetate/methanol (4:1)). The title compound was crystallized as theoxalate salt from acetone to yield 430 mg. (M.p. 189°-190° C.; M⁺ : 181;Compound 36).

EXAMPLE 341,2,5,6-Tetrahydro-3-(3-hexyloxy-1,2,5-thiadiazol-4-yl)pyridine oxalate

To a solution of3-(3-hexyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine(0.70 g, 2.4 mmol) in 1,2-dichloroethane (20 ml) was added a solution of1-chloroethyl-chloroformate (0.35 g, 2.4 mmol) in 1,2-dichloroethane at0° C. The reaction mixture was heated to 40° C. for 2 h and evaporated.The residue was dissolved in methanol and heated to reflux for1 h andevaporated. The residue was dissolved in diluted sodium hydroxide andextracted with ether. The combined ether phases were dried andevaporated. Crystallization as the oxalate salt from acetone gave thetitle compound in 72% (620 mg) yield. (M.p. 157°-159° C.; M⁺ : 267;Compound 37).

In exactly the same manner the following compounds were prepared:

3-(3-Ethoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydropyridinehydrochloride. M.p. 217°-218° C. Compound 215.

3-(3-Ethylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydropyridinehydrochloride. M.p. 181°-182° C. Compound 216.

3-(3-Propylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydropyridineoxalate. M.p. 190°-191° C. Compound 217.

3-(3-Butylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydropyridineoxalate. M.p. 182°-183° C. Compound 218.

3-(3-Pentylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydropyridineoxalate. M.p. 181°-182° C. Compound 219.

3-(3-Hexylthio-1,2,5-thiadiazol-4-yl-1,2,5,6-tetrahydropyridine oxalate.M.p. 173°-175° C. Compound 220.

3-(3-(4-Pentynylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydropyridineoxalate. M.p. 140°-142° C. Compound 221.

3-(3-(2,2,2-Trifluoroethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydropyridinehydrochloride. M.p. 105°-110° C. Compound 222.

3-(3-(2,2,2-Trifluoroethoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydropyridinehydrochloride. M.p. 149°-151° C. Compound 223.

3-(3-(2-Phenoxyethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydropyridineoxalate.M.p. 191°-192° C. Compound 224.

EXAMPLE 35

A. 3-(3-(2-(2-Methoxyethoxy)ethoxy)-1,2,5-thiadiazol-4-yl)pyridine

To a solution of sodium (210 mg, 9 mmol) in 2-(2-methoxyethoxy)ethanol(10 ml) was added 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (590 mg, 3mmol).The mixture was stirred at 50° C. for 4 h and evaporated. Theresidue was dissolved in water and extracted with ether. The combinedorganic phases were dried and evaporated to give the title compound.

B.3-(3-(2-(2-Methoxyethoxy)ethoxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridiniumiodide

A mixture of methyl iodide (0.5 ml, 9 mmol) and3-(3-(2-(2-methoxyethoxy)ethoxy)-1,2,5-thiadiazol-4-yl)pyridine (3 mmol)in acetone (10 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtrationtoyield 0.76 g (60%).

C.3-(3-(2-(2-Methoxyethoxy)ethoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (150 mg, 4 mmol) was added to a solution of3-(3-(2(2-methoxyethoxy)ethoxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridiniumiodide (0.76 g, 1.8 mmol) in ethanol (99.9%, 20 ml) and the reactionmixture was stirred at -10° C. for 1 h. After evaporation the residuewas dissolved in water and extracted with ethyl acetate. Thedriedorganic phases were evaporated and the residue purified by columnchromatography (SiO₂, eluent: ethyl acetate/methanol (4:1)). The titlecompound was crystallized as the oxalate salt from acetone to yield 70mg. (M.p. 142°-143° C.; M⁺ : 299; Compound 38).

EXAMPLE 36

A. 3-(3-(3-Ethoxy-1-propoxy)-1,2,5-thiadiazol-4-yl)pyridine

To a solution of 3-ethoxy-1-propanol (940 mg, 9 mmol) and sodium hydride(310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (590 mg, 3 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 2 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to give the title compound.

B. 3-(3-(3-Ethoxy-1-propoxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridiniumiodide

A mixture of methyl iodide (0.5 ml, 9 mmol) and3-(3-ethoxy-1-propoxy-1,2,5-thiadiazol-4-yl)pyridine (3 mmol) in acetone(5 ml) was stirred at room temperature for 18 h. The title compoundprecipitated from the solution and was collected by filtration.

C.3-(3-(3-Ethoxy-1-propoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (190 mg, 5 mmol) was added to a solution of3-(3-(3-ethoxy-1-propoxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridiniumiodide(3 mmol) in ethanol (99.9%, 15 ml) and the reaction mixture wasstirred at -10° C. for 1 h. After evaporation the residue was dissolvedin water and extracted with ethyl acetate. The dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallizedas the oxalate salt from acetone to yield 210 mg. (M.p.149°-150° C.; M⁺ : 283; Compound 39).

EXAMPLE 37

A. 3-(3-(2-Ethoxyethoxy)-1,2,5-thiadiazol-4-yl)pyridine

To a solution of 2-ethoxyethanol (1.08 g, 12 mmol) and sodium hydride(410 mg, 12 mmol) in dry tetrahydrofuran was added a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (790 mg, 4 mmol) in drytetrahydrofuran. The mixture was stirred at room temperature for 2 h.Water was added and the mixture was extracted with ether. The etherphase was dried and evaporated to give the title compound.

B. 3-(3-(2-Ethoxyethoxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridiniumiodide

A mixture of methyl iodide (0.5 ml, 9 mmol) and3-(3-(2-ethoxyethoxy)-1,2,5-thiadiazol-4-yl)pyridine (4 mmol) in acetone(3 ml) was stirred at room temperature for 18 h. The title compoundprecipitated from the solution and was collected by filtration to yield1.45 g (92%).

C.3-(3-(2-Ethoxyethoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (350 mg, 9 mmol) was added to a solution of3-(3-(2-ethoxyethoxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide(1.45 g, 3.7 mmol) in ethanol (99.9%, 15 ml) and the reaction mixturewas stirred at -10° C. for 1 h. After evaporation the residue wasdissolved in water and extracted with ethyl acetate. The dried organicphases were evaporated and the residue purified by column chromatography(SiO₂, eluent: ethyl acetate/ methanol (4:1)). The title compoundwascrystallized as the oxalate salt from acetone to yield 640 mg. (M.p.153°-156° C.; M⁺ : 269; Compound 40).

EXAMPLE 38

A. 3-(3-(2-Butoxyethoxy)-1,2,5-thiadiazol-4-yl)pyridine

To a solution of 2-butoxyethanol (1.06 g, 9 mmol) and sodium hydride(310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (590 mg, 3 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 2 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to give the title compound.

B. 3-(3-(2-Butoxyethoxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridiniumiodide

A mixture of methyl iodide (0.5 ml, 9 mmol) and3-(3-(2-butoxyethoxy)-1,2,5-thiadiazol-4-yl)pyridine (3 mmol) in acetone(4 ml) was stirred at room temperature for 18 h. The title compoundprecipitated from the solution and was collected by filtration to yield1.07 g (85%).

C.3-(3-(2-Butoxyethoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (230 mg, 6 mmol) was added to a solution of3-(3-(2-butoxyethoxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide(1.07 g, 2.5 mmol) in ethanol (99.9%, 20 ml) and the reaction mixturewas stirred at -10° C. for 1 h. After evaporation the residue wasdissolved in water and extracted with ethyl acetate. The dried organicphases were evaporated and the residue purified by column chromatography(SiO₂, eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 490 mg. (M.p.152°-153° C.; M⁺ : 297; Compound 41).

EXAMPLE 39

A. 3-(3-(2-(2-Butoxyethoxy)ethoxy)-1,2,5-thiadiazol-4-yl)pyridine

To a solution of 2-(2-butoxyethoxy)ethanol (1.46 g, 9 mmol) and sodiumhydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (590 mg, 3 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 1 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to give the title compound.

B.3-(3-(2-(2-Butoxyethoxy)ethoxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridiniumiodide

A mixture of methyl iodide (0.5 ml, 9 mmol) and3-(3-(2-(2-butoxyethoxy)ethoxy)-1,2,5-thiadiazol-4-yl)pyridine (3 mmol)inacetone (5 ml) was stirred at room temperature for 18 h. The titlecompoundprecipitated from the solution and was collected by filtration.

C.3-(3-(2-(2-Butoxyethoxy)ethoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro1-methylpyridineoxalate

Sodium borohydride (230 mg, 6 mmol) was added to a solution of3-(3-(2(2-butoxyethoxy)ethoxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridiniumiodide (3 mmol) in ethanol (99.9%, 20 ml) and the reaction mixture wasstirred at -10° C. for 1 h. After evaporation the residue was dissolvedin water and extracted with ethyl acetate. The dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 340 mg. (M.p.90°-91° C.; M⁺ : 341; Compound 42).

EXAMPLE 40

A. 3-(3-(2-(2-Ethoxyethoxy)ethoxy)-1,2,5-thiadiazol-4-yl)pyridine

To a solution of 2-(2-ethoxyethoxy)ethanol (1.21 g, 9 mmol) and sodiumhydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (590 mg, 3 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 2 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to give the title compound.

B.3-(3-(2-(2-Ethoxyethoxy)ethoxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridiniumiodide

A mixture of methyl iodide (0.5 ml, 9 mmol) and3-(3-(2-(2-ethoxyethoxy)ethoxy)-1,2,5-thiadiazol-4-yl)pyridine (3 mmol)inacetone (5 ml) was stirred at room temperature for 18 h. The titlecompoundprecipitated from the solution and was collected by filtration.

C.3-(3-(2-(2-Ethoxyethoxy)ethoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1methylpyridineoxalate

Sodium borohydride (230 mg, 6 mmol) was added to a solution of3-(3-(2-(2-ethoxyethoxy)ethoxy)-1,2,5-thiadiazol-4-yl)-1-methylpyridiniumiodide (3 mmol) in ethanol (99.9%, 20 ml) and the reaction mixture wasstirred at -10° C. for 1 h. After evaporation the residue was dissolvedin water and extracted with ethyl acetate. The dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 290 mg. (M.p.115°-116° C.; M⁺ : 313; Compound 43).

EXAMPLE 41

A. 3-(3-(4-Methylpiperidino)-1,2,5-thiadiazol-4-yl)pyridine

A solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (10.80 g, 4mmol) and 4-methylpiperidine (1.96 g, 20 mmol) in DMF (10 ml) was heatedat 100° C. for 3 h. After evaporation water was added to the residue andextracted with ether. The combined and dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methylene chloride (1:2)). Yield: 0.8 g (77%).

B. 3-(3-(4-Methylpiperidino)-1,2,5-thiadiazol-4-yl)-1-methylpyridiniumiodide

A mixture of methyl iodide (0.5 ml, 8 mmol) and3-(3-(4-methylpiperidino)-1,2,5-thiadiazol-4-yl)pyridine (0.8 g, 3.1mmol)in acetone (5 ml) was stirred at room temperature for 18 h. Thetitle compound precipitated from the solution and was collected byfiltration toyield 1.14 g (92%).

C.3-(3-(4-Methylpiperidino)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (270 mg, 7 mmol) was added to a solution of3-(3-(4-methylpiperidino)-1,2,5-thiadiazol-4-yl)-1-methylpyridiniumiodide(1.14 g, 2.8 mmol) in ethanol (99.9%, 20 ml) and the reactionmixture was stirred at -10° C. for 1 h. After evaporation the residuewas dissolved in water and extracted with ethyl acetate. The driedorganic phases were evaporated and the residue purified by columnchromatography (SiO₂, eluent: ethyl acetate/methanol (4:1)). The titlecompound was crystallized as the oxalate salt from acetone to yield 450mg. (M.p. 106°-107° C.; M⁺ : 278; Compound 44).

EXAMPLE 42

A. 3-(3-Morpholino-1,2,5-thiadiazol-4-yl)pyridine

A solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (0.59 g, 3mmol) and morpholine (1.3 g, 15 mmol) in DMF (5 ml) was heated at 100°C.for 3 h. After evaporation water was added to the residue andextracted with ether. The combined and dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methylene chloride (1:1)). Yield: 0.68 g (91%).

B. 3-(3-Morpholino-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (0.5 ml, 8 mmol) and3-(3-morpholino-1,2,5-thiadiazol-4-yl)pyridine (680 mg, 2.7 mmol) inacetone (5 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtrationtoyield 1.0 g (94%).

C.3-(3-Morpholino-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (380 mg, 10 mmol) was added to a solution of3-(3-morpholino-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide (1.53g, 39 mmol) in ethanol (99.9%, 30 ml) and the reaction mixture wasstirred at -10° C. for 1 h. After evaporation the residue was dissolvedin water and extracted with ethyl acetate. The dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallizedas the oxalate salt from acetone to yield 470 mg. (M.p.177°-178° C.; M⁺ : 266; Compound 45).

EXAMPLE 43

A. 3-(3-Hexylamino-1,2,5-thiadiazol-4-yl)pyridine

A solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (0.59 g, 3mmol) and hexylamine (1.52 g, 15 mmol) in DMSO (5 ml) was heated at 100°C. for 48 h. After evaporation, water was added to the residue andextracted with ether. The combined organic extracts were dried andevaporated to give the title compound.

B. 3-(3-Hexylamino-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (0.6 ml, 9.6 mmol) and3-(3-hexylamino-1,2,5-thiadiazol-4-yl)pyridine (3.2 mmol) in acetone (5ml) was stirred at room temperature for 18 h and evaporated.

C.3-(3-Hexylamino-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (380 mg, 10 mmol) was added to a solution of3-(3-hexylamino-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide (4.2mmol) in ethanol (99.9%, 25 ml) and the reaction mixture was stirred at-10° C. for 1 h. After evaporation the residue was dissolved in waterand extracted with ethyl acetate. The dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallizedas the oxalate salt from acetone to yield 490 mg. (M.p.102°-103° C.; M⁺ : 280; Compound 46).

EXAMPLE 44

A. 3-(3-Propylthio-1,2,5-thiadiazol-4-yl)pyridine

Sodium hydrogen sulfide (220 mg, 3 mmol) was added over 30 min. to asolution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (0.59 g, 3 mmol)inDMF (20 ml) at room temperature. Potassium carbonate (1.24 g, 9 mmol)and iodopropan (0.76 g, 4.5 mmol) were added. The reaction mixture wasstirredat room temperature for 30 min. Water was added and the mixtureextracted with ether. The combined ether phases were dried andevaporated to give the title compound in 89% (0.63 g) yield.

B. 3-(3-Propylthio-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (0.5 ml, 8 mmol) and3-(3-propylthio-1,2,-5-thiadiazol-4-yl)pyridine (0.63 g, 2.6 mmol) inacetone (5 ml) was stirred at room temperature for 18 h and evaporated.

C. 3-(3-Propylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine oxalate

Sodium borohydride (200 mg, 5 mmol) was added to a solution of3-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide (2.6mmol) in ethanol (99.9%, 15 ml) and the reaction mixture was stirred at-10° C. for 1 h. After evaporation the residue was dissolved in waterand extracted with ethyl acetate. The dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methanol (4:1)).The title compound wascrystallized as the oxalate salt from acetone to yield 310 mg. (M.p.138°-139° C.; M⁺ : 255; Compound 47).

EXAMPLE 45

A. 3-(3-Butylthio-1,2,5-thiadiazol-4-yl)pyridine

Sodium hydrogen sulfide (0.5 g, 6.8 mmol) was added to a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (0.5 g, 2.5 mmol) in DMF (20ml) at room temperature and the reaction mixture was stirred for 30 min.Potassium carbonate (2 g, 14.5 mmol) and butyl iodide (1 ml, 8.8 mmol)were added and the reaction mixture was stirred for additionally 10 min.Water (50 ml) was added and extracted with ether. The combined etherphases were dried and evaporated to give the title compound. Yield: 0.6g.

B. 3-(3-Butylthio-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide

Methyl iodide (1 ml, 15 mmol) was added to a solution of3-(3-butylthio-1,2,5-thiadiazol-4-yl)pyridine (0.6 g, 2.3 mmol) and thereaction mixture was stirred at room temperature for 48 h andevaporated.

C.3-(3-Butylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (250 mg, 6.2 mmol) was added to a solution of3-(3-butylthio-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide (2.3mmol)in ethanol (99.9%, 20 ml) and the reaction mixture was stirred at0°C. for 1 h. After evaporation the residue was dissolved in water andextracted with ethyl acetate. The dried organic phases were evaporatedandthe residue purified by column chromatography (SiO₂, eluent: ethylacetate/methanol (4:1)). The title compound was crystallized as theoxalate salt from acetone to yield 300 mg. (M.p. 148°-150° C.; M⁺ : 269;Compound 48).

EXAMPLE 46

A. 3-(3-Methylthio-1,2,5-thiadiazol-4-yl)pyridine

Sodium hydrogen sulfide (0.5 g, 6.8 mmol) was added to a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (0.5 g, 2.5 mmol) in DMF (20ml) at room temperature and the reaction mixture was stirred for 30 min.Potassium carbonate (2 g, 14.5 mmol) and methyl iodide (1 ml, 15 mmol)were added and the reaction mixture was stirred for additionally 10 min.Water (50 ml) was added and extracted with ether. The combined etherphases were dried and evaporated to give the title compound. Yield: 0.5g.

B. 3-(3-Methylthio-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide

Methyl iodide (1 ml, 15 mmol) was added to a solution of3-(3-methylthio-1,2,5-thiadiazol-4-yl)pyridine (0.5 g, 2.3 mmol) and thereaction mixture was stirred at room temperature for 48 h andevaporated.

C.3-(3-Methylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (250 mg, 6.2 mmol) was added to a solution of3-(3-methylthio-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide (2.3mmol) in ethanol (99.9%, 20 ml) and the reaction mixture was stirred at0° C. for 1 h. After evaporation the residue was dissolved in waterandextracted with ethyl acetate. The dried organic phases were evaporatedand the residue purified by column chromatography (SiO₂, eluent: ethylacetate/methanol (4:1)). The title compound was crystallized as theoxalate salt from acetone to yield 300 mg. (M.p. 169°-170° C.; M⁺ : 227;Compound 49).

EXAMPLE 47

A. Alpha-oximido-3-pyridylacetonitrile

3-pyridylacetonitrile (47.2 g, 400 mmol) was dissolved in a solution ofsodium hydroxide (16 g, 400 mmol) in methanol (100 ml). Methylnitrite,generated by dropping a solution of concentrated sulphuric acid (12.8ml) and water (26 ml) to a solution of sodium nitrite (33.2 g, 480 mmol)in water (20 ml) and methanol (20 ml), was bobled through the3-pyridylacetonitrile solution at 0° C. The reaction mixture was stirredat 0° C. for 1 h and the precipitate collected by filtration. Theprecipitate was washed with a little methanol to give the wanted productin 70% (41.1 g) yield. M⁺ : 147.

B. Alpha-oximido-3-pyridylacetamidoxime

A mixture of alpha-oximido-3-pyridylacetonitrile (41.0 g, 279 mmol),hydroxylamine hydrochloride (21.5 g, 310 mmol) and sodium acetate (50.8g,620 mmol) in ethanol (99.9%, 500 ml) was refluxed for 4 h. Aftercooling, the precipitate was collected by filtration and dried. Theprecipitate contained the wanted product and sodium acetate (85 g,168%); M⁺ : 180.

C. 3-(3-Amino-1,2,5-oxadiazol-4-yl)pyridine

Crude alpha-oximido-3-pyridylacetamidoxime (5 g) and phosphoruspentachloride (5 g) was refluxed in dry ether (250 ml) for 6 h. Waterand potassium carbonate to alkaline pH was added and the phasesseparated. Theaqueous phase was extracted with ether and the combinedether phases dried.Evaporation of the ether phases gave the titlecompound in 850 mg yield; M⁺ : 162.

D. 3-(3-Amino-1,2,5-oxadiazol-4-yl)-1-methylpyridinium iodide

To a solution of 3-(3-amino-1,2,5-oxadiazol-4-yl)pyridine (870 mg, 5.3mmol) in acetone (20 ml) was added methyl iodide (990 μl, 16 mmol) andthe reaction mixture was stirred overnight at room temperature. Thetitle compound precipitated and was collected by filtration (1.1 g,69%).

E. 3-(3-Amino-1,2,5-oxadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (262 mg, 6.9 mmol) was added to a solution of3-(3-amino-1,2,5-oxadiazol-4-yl)-1-methylpyridinium iodide (1.05 g, 3.45mmol) in methanol (80 ml) at 0° C. After 15 min. water (40 ml) was addedand the mixture extracted with ether. The ether phase was dried,evaporated and purified by column chromatography (eluent: ethylacetate:methanol (2:1)). Crystallization from acetone with oxalic acidgave the title compound in 310 mg (50%) yield. (M.p. 181°-183° C.; M⁺ :180; Compound 50).

EXAMPLE 48

A. 3-(3-Acetylamino-1,2,5-oxadiazol-4-yl)pyridine

Crude hydroxyimino-3-pyridylmethylamidoxime (4.5 g) and polyphosphoricacid(49 g) was stirred at 100° C. for 18 h. After cooling to roomtemperature aqueous ammonia (25%) was added slowly to pH>9 and theprecipitate collected by filtration. The precipitate was dissolved inwater and extracted with methylene chloride. The organic phases weredriedand evaporated to give the title compound in 430 mg yield.

B. 3-(3-Acetylamino-1,2,5-oxadiazol-4-yl)-1-methylpyridinium iodide

Methyl iodide (450 μl, 7.2 mmol) was added to a solution of3-(3-acetylamino-1,2,5-oxadiazol-4-yl)pyridine (490 mg, 2.4 mmol) inacetone. The reaction mixture was stirred at room temperature for 18 handthe precipitate collected by filtration. Yield: 640 mg (77%).

C.3-(3-Acetylamino-1,2,5-oxadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (140 mg, 3.7 mmol) was added to a solution of3-(3-acetylamino-1,2,5-oxadiazol-4-yl)-1-methylpyridinium iodide (640mg, 1.85 mmol) in methanol (15 ml) at 0° C. After 15 min. water (10ml)was added and the reaction mixture extracted with ether. The combinedetherphases were dried and evaporated. Crystallization from acetone withoxalic acid gave the title compound in 140 mg yield. (M.p. 180°-184° C.;M⁺ : 222; Compound 51).

EXAMPLE 49

A. 3-(1,2,5-Oxadiazol-3-yl)pyridine and3-(3-chloro-1,2,5-oxadiazol-4-yl)pyridine

To a solution of 3-(3-amino-1,2,5-oxadiazol-4-yl)pyridine (1.0 g, 6.2mmol)in glacial acetic acid (16 ml) and concentrated hydrochloric acid(5.2 ml) was added CuCl₂ (938 mg, 7 mmol) and cupper coils (100 mg) at0° C. After 10 min. a solution of sodium nitrite (483 mg, 7 mmol) inwater (3 ml) was added dropwise at 5° C. The reaction mixture wasstirred additionally 30 min. at 0° C. Aqueous sodium hydroxide (2N) wasadded to alkaline pH and the mixture extracted with ether. The etherphases were dried and evaporated to give a mixture of the titlecompounds. Separation by column chromatography (SiO₂, eluent: ethylacetate) gave the chloro compound, upper spot, in 230 mg yield, and theunsubstituted product, lower spot, in 60 mg yield.

B. 3-(3-Chloro-1,2,5-oxadiazol-4-yl)-1-methylpyridinium iodide

Methyl iodide (1 ml, 15 mmol) was added to a solution of3-(3-chloro-1,2,5-oxadiazol-4-yl)pyridine (230 mg, 1.2 mmol) in acetone.The reaction mixture was stirred at room temperature for 18 h andevaporated to give the title compound.

C. 3-(3-Chloro-1,2,5-oxadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (119 mg, 3.2 mmol) was added to a solution of3-(3-chloro-1,2,5-oxadiazol-4-yl)-1-methylpyridinium iodide (1.2 mmol)in methanol (5 ml) at 0° C. After 15 min. water was added and themixture extracted with ether. The ether phases were dried andevaporated. Crystallization from acetone with oxalic acid andrecrystallization from acetone gave the title compound in 60 mg yield.(M.p. 126°-129° C.; M⁺ : 198 and 200; Compound 52).

EXAMPLE 50

A. 3-(1,2,5-Oxadiazol-3-yl)-1-methylpyridinium iodide

Methyl iodide (1 ml, 15 mmol) was added to a solution of3-(1,2,5-oxadiazol-3-yl)pyridine (430 mg, 2.9 mmol) in acetone (20 ml).The reaction mixture was stirred at room temperature for 18 h. Theproductprecipitated from the solution and the title compound wascollected by filtration in 82% (700 mg) yield.

B. 3-(1,2,5-Oxadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine oxalate

Sodium borohydride (168 mg, 4.4 mmol) was added to a solution of3-(1,2,5-oxadiazol-3-yl)-1-methylpyridinium iodide (640 mg, 2.2 mmol) inmethanol (15 ml) and water (2 ml) at 0° C. After 15 min. water was addedand the mixture extracted with ether. The combined ether phasesweredried and evaporated. The residue was crystallized as the oxalatesalt fromacetone giving the title compound in 100 mg yield. (M.p.238°-240° C. dec.; M⁺ : 165; Compound 53).

EXAMPLE 51

A. 3-(3-Hexyloxy-1,2,5-oxadiazol-4-yl)pyridine

To a solution of sodium (100 mg, 4.3 mmol) in 1-hexanol (10 ml) wasadded 3-(3-chloro-1,2,5-oxadiazol-4-yl)pyridine (180 mg, 1 mmol). Themixture was stirred at 25° C. for 18 h and evaporated. The residue wasdissolved in water and extracted with ether. The combined organic phaseswere dried and evaporated to give the title compound.

B. 3-(3-Hexyloxy-1,2,5-oxadiazol-4-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (1 ml, 15 mmol) and3-(3-hexyloxy-1,2,5-oxadiazol-4-yl)pyridine (1 mmol) in acetone (5 ml)wasstirred at room temperature for 18 h and evaporated to give the titlecompound.

C.3-(3-Hexyloxy-1,2,5-oxadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (76 mg, 2 mmol) was added to a solution of3-(3-hexyloxy-1,2,5-oxadiazol-4-yl)-1-methylpyridinium iodide (1 mmol)in methanol (5 ml) and the reaction mixture was stirred at 0° C. for 15min. After evaporation the residue was dissolved in water andextractedwith ether. The dried organic phases were evaporated and theresidue purified by column chromatography (SiO₂, eluent: ethylacetate/methanol (4:1)). The title compound was crystallized as theoxalate salt from acetone to yield 60 mg. (M.p. 143°-147° C.; M⁺ : 265;Compound 54).

EXAMPLE 52

A. 3-(3-Butyloxy-1,2,5-oxadiazol-4-yl)pyridine

To a solution of sodium (150 mg, 6.5 mmol) in 1-butanol (5 ml) was added3-(3-chloro-1,2,5-oxadiazol-4-yl)pyridine (350 mg, 1.9 mmol). Themixture was stirred at 25° C. for 2 h and evaporated. The residue wasdissolved in water and extracted with ether. The combined organic phaseswere dried and evaporated to give the title compound.

B. 3-(3-Butyloxy-1,2,5-oxadiazol-4-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (1 ml, 15 mmol) and3-(3-butyloxy-1,2,5-oxadiazol-4-yl)pyridine (1.9 mmol) in acetone (10ml) was stirred at room temperature for 18 h and evaporated.

C.3-(3-Butyloxy-1,2,5-oxadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (148 mg, 3.8 mmol) was added to a solution of3-(3-butyloxy-1,2,5-oxadiazol-4-yl)-1-methylpyridinium iodide (1.9 mmol)in methanol (20 ml) and the reaction mixture was stirred at 0° C. for 15min. After evaporation the residue was dissolved in water and extractedwith ether. The dried organic phases were evaporated and the residuepurified by column chromatography (SiO₂, eluent: ethyl acetate/methanol(4:1)). The title compound was crystallized as the oxalate salt fromacetone to yield 120 mg. (M.p. 132°-135° C.; M⁺ : 237; Compound 55).

EXAMPLE 53

A. 3-(3-(3-Hexynyloxy)-1,2,5-oxadiazol-4-yl)pyridine

To a solution of 3-hexyn-1-ol (980 mg, 10 mmol) and sodium hydride (240mg,10 mmol) in dry tetrahydrofuran was added a solution of3-(3-chloro-1,2,5-oxadiazol-4-yl)pyridine (450 mg, 2.5 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 2 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to give the title compound.

B. 3-(3-(3-Hexynyloxy)-1,2,5-oxadiazol-4-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (1.5 ml, 22 mmol) and3-(3-(3-hexynyloxy)-1,2,5-oxadiazol-4-yl)pyridine (2.5 mmol) in acetone(20 ml) was stirred at room temperature for 18 h and evaporated to givethe title compound.

C.3-(3-(3-Hexynyloxy)-1,2,5-oxadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (190 mg, 5 mmol) was added to a solution of3-(3-(3-hexynyloxy)-1,2,5-oxadiazol-4-yl)-1-methylpyridinium iodide (2.5mmol) in methanol (20 ml) and the reaction mixture was stirred at 0° C.for 15 min. After evaporation the residue was dissolved in water andextracted with ether. The dried organic phases were evaporated and theresidue purified by column chromatography (SiO₂, eluent: ethylacetate/methanol (4:1)). The title compound was crystallized as theoxalate salt from acetone to yield 50 mg. (M.p. 159°-161° C.; M⁺ : 261;Compound 56).

EXAMPLE 543-(3-Pentyl-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridiniumoxalate

To a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine(450 mg, 1.5 mmol) in tetrahydrofuran (20 ml) was added slowly asolution of pentylmagnesium bromide (1.5 mmol) in tetrahydrofuran at 0°C. The reaction mixture was stirred for 10 min. and water (20 ml) wasadded. The product was extracted with ether (3×100 ml) and the driedether phases evaporated. The residue was crystallized as the oxalatesalt from acetone in 300 mg (58%) yield. Recrystallization from ethanolgave the title compound in 125 mg (24%) yield. (M.p. 156°-157° C.; M⁺ :251; Compound 57).

EXAMPLE 553-(3-Heptyl-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridiniumoxalate

To a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine(450 mg, 1.5 mmol) in tetrahydrofuran (20 ml) was added slowly asolution of heptylmagnesium bromide (1.5 mmol) in tetrahydrofuran at 0°C. The reaction mixture was stirred for 10 min. and water (20 ml) wasadded. The product was extracted with ether (3×100 ml) and the driedether phases evaporated. The residue was crystallized as the oxalatesalt from acetone in 400 mg (73%) yield. (M.p. 151°-152° C.; M⁺ :274;Compound 58).

EXAMPLE 563-(3-(5-Hexenyl)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridiniumoxalate

To a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine(450 mg, 1.5 mmol) in tetrahydrofuran (20 ml) was added slowly asolution of 5-hexenylmagnesium bromide (1.5 mmol) in tetrahydrofuran at0° C. The reaction mixture was stirred for 10 min. and water (20 ml) wasadded. The product was extracted with ether (3×100 ml) and thedriedether phases evaporated. The residue was purified by columnchromatography (SiO₂, eluent: ethyl acetate/methanol (4:1)). The titlecompound was crystallized as the oxalate salt from acetone in 340 mg(64%) yield. (M.p.113°-115° C.; M⁺ : 263; Compound 59).

EXAMPLE 573-(3-Octyl-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridiniumoxalate

To a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine(450 mg, 1.5 mmol) in tetrahydrofuran (20 ml) was added slowly asolution of octylmagnesium bromide (1.5 mmol) in tetrahydrofuran at 0°C. The reaction mixture was stirred for 10 min. and water (20 ml) wasadded. The product was extracted with ether (3×100 ml) and the driedether phases evaporated. The residue was purified by columnchromatography (SiO₂, eluent: ethyl acetate/methanol (4:1)). The titlecompound was crystallized as the oxalate salt from acetone in 430 mg(75%) yield. (M.p.157°-158° C.; M⁺ : 293; Compound 60).

EXAMPLE 583-(3-Isobutyl-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridiniumoxalate

To a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine(300 mg, 1.5 mmol) in tetrahydrofuran (20 ml) was added slowly asolution of isobutylmagnesium bromide (1.5 mmol) in tetrahydrofuran at0° C.The reaction mixture was stirred for 10 min. and water (20 ml) wasadded. The product was extracted with ether (3×100 ml) and the driedether phases evaporated. The residue was purified by columnchromatography (SiO₂, eluent: ethyl acetate/methanol (4:1)). The titlecompound was crystallized as the oxalate salt from acetone in 350 mg(76%) yield. (M.p.148°-149° C.; M⁺ : 237; Compound 61).

EXAMPLE 593-(3-Cyclopropylmethyl-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridiniumoxalate

To a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine(300 mg, 1.4 mmol) in tetrahydrofuran (20 ml) was added slowly asolution of cyclopropylmethylmagnesium bromide (1.5 mmol) intetrahydrofuran at 0° C. The reaction mixture was stirred for 10 min.and water (20 ml) was added. The product was extracted with ether (3×100ml) and the dried ether phases evaporated. The residue was purified bycolumn chromatography (SiO₂, eluent: ethyl acetate/methanol (4:1)). Thetitle compound was crystallized as the oxalate salt from acetone in 380mg(83%) yield. (M.p. 147°-148° C.; M⁺ : 235; Compound 62).

EXAMPLE 603-(3-Propyl-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridiniumoxalate

To a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine(450 mg, 1.5 mmol) in tetrahydrofuran (20 ml) was added slowly asolution of propylmagnesium bromide (1.5 mmol) in tetrahydrofuran at 0°C. The reaction mixture was stirred for 10 min. and water (20 ml) wasadded. The product was extracted with ether (3×100 ml) and the driedether phases evaporated. The residue was crystallized as the oxalatesalt from acetone in 350 mg (75%) yield. (M.p. 141°-142° C.; M⁺ :223;Compound 63).

EXAMPLE 61

A. 3-(3-Octylthio-1,2,5-thiadiazol-4-yl)pyridine

Sodium hydrogen sulfide (0.25 g, 3.3 mmol) was added to a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (0.59 g, 3 mmol) in DMF (20ml)at room temperature and the reaction mixture was stirred for 30 min.Potassium carbonate (1.24 g, 9 mmol) and 1-bromooctane (0.80 ml, 4.5mmol)were added and the reaction mixture was stirred for additionally 10min. Water (50 ml) was added and extracted with ether. The combinedether phases were dried and evaporated to give the title compound.

B. 3-(3-Octylthio-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide

Methyl iodide (0.5 ml, 7.5 mmol) was added to a solution of3-(3-octylthio-1,2,5-thiadiazol-4-yl)pyridine (3 mmol) and the reactionmixture was stirred at room temperature for 48 h and evaporated.

C.3-(3-Octylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (270 mg, 7 mmol) was added to a solution of3-(3-octylthio-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide (3 mmol)in ethanol (99.9%, 20 ml) and the reaction mixture was stirred at 0° C.for 1 h. After evaporation the residue was dissolved in waterandextracted with ethyl acetate. The dried organic phases were evaporatedand the residue purified by column chromatography (SiO₂, eluent: ethylacetate/methanol (4:1)). The title compound was crystallized as theoxalate salt from acetone to yield 400 mg. (M.p. 121°-122° C.; M⁺ : 325;Compound 64).

EXAMPLE 62

A. 3-(3-Ethylthio-1,2,5-thiadiazol-4-yl)pyridine

Sodium hydrogen sulfide (0.25 g, 3.3 mmol) was added to a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (0.59 g, 3 mmol) in DMF (20ml)at room temperature and the reaction mixture was stirred for 30 min.Potassium carbonate (1.24 g, 9 mmol) and ethyl iodide (0.36 ml, 4.5mmol) were added and the reaction mixture was stirred for additionally10 min. Water (50 ml) was added and extracted with ether. The combinedether phases were dried and evaporated to give the title compound.

B. 3-(3-Ethylthio-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide

Methyl iodide (0.5 ml, 7.5 mmol) was added to a solution of3-(3-ethylthio-1,2,5-thiadiazol-4-yl)pyridine (3 mmol) and the reactionmixture was stirred at room temperature for 48 h and evaporated.

C.3-(3-Ethylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (270 mg, 7 mmol) was added to a solution of3-(3-ethylthio-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide (3 mmol)in ethanol (99.9%, 20 ml) and the reaction mixture was stirred at 0° Cfor 1 h. After evaporation the residue was dissolved in water andextracted with ethyl acetate. The dried organic phases wereevaporatedand the residue purified by column chromatography (SiO₂,eluent: ethylacetate/methanol (4:1)). The title compound wascrystallized as the oxalatesalt from acetone to yield 490 mg. (M.p.145°-146° C.; M⁺ : 241; Compound 65).

EXAMPLE 63

A. 3-(3-Pentylthio-1,2,5-thiadiazol-4-yl)pyridine

Sodium hydrogen sulfide (0.25 g, 3.3 mmol) was added to a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (0.59 g, 3 mmol) in DMF (20ml)at room temperature and the reaction mixture was stirred for 30 min.Potassium carbonate (1.24 g, 9 mmol) and pentyl bromide (700 mg, 4.5mmol)were added and the reaction mixture was stirred for additionally 10min. Water (50 ml) was added and extracted with ether. The combinedether phases were dried and evaporated to give the title compound.

B. 3-(3-Pentylthio-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide

Methyl iodide (0.5 ml, 7.5 mmol) was added to a solution of3-(3-pentylthio-1,2,5-thiadiazol-4-yl)pyridine (3 mmol) and the reactionmixture was stirred at room temperature for 48 h and evaporated.

C.3-(3-Pentylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (300 mg, 8 mmol) was added to a solution of3-(3-pentylthio-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide (3mmol) in ethanol (99.9%, 20 ml) and the reaction mixture was stirred at0° C. for 1 h. After evaporation the residue was dissolved in waterandextracted with ethyl acetate. The dried organic phases were evaporatedand the residue purified by column chromatography (SiO₂, eluent: ethylacetate/methanol (4:1)). The title compound was crystallized as theoxalate salt from acetone to yield 430 mg. (M.p. 136°-138° C.; M⁺ : 283;Compound 66).

EXAMPLE 64

A. 3-(3-Hexylthio-1,2,5-thiadiazol-4-yl)pyridine

Sodium hydrogen sulfide (0.25 g, 3.3 mmol) was added to a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (0.59 g, 3 mmol) in DMF (20ml)at room temperature and the reaction mixture was stirred for 30 min.Potassium carbonate (1.24 g, 9 mmol) and hexyl bromide (0.63 ml, 4.5mmol)were added and the reaction mixture was stirred for additionally 10min. Water (50 ml) was added and extracted with ether. The combinedether phases were dried and evaporated to give the title compound.

B. 3-(3-Hexylthio-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide

Methyl iodide (1 ml, 15 mmol) was added to a solution of3-(3-hexylthio-1,2,5-thiadiazol-4-yl)pyridine (3 mmol) and the reactionmixture was stirred at room temperature for 48 h and evaporated.

C.3-(3-Hexylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (230 mg, 6 mmol) was added to a solution of3-(3-hexylthio-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide (3 mmol)in ethanol (99.9%, 20 ml) and the reaction mixture was stirred at 0° C.for 1 h. After evaporation the residue was dissolved in waterandextracted with ethyl acetate. The dried organic phases were evaporatedand the residue purified by column chromatography (SiO₂, eluent: ethylacetate/methanol (4:1)). The title compound was crystallized as theoxalate salt from acetone to yield 350 mg. (M.p. 126°-127° C.; M⁺ : 297;Compound 67).

EXAMPLE 65

A. 3-(3-(5-Cyanopentylthio)-1,2,5-thiadiazol-4-yl)pyridine

Sodium hydrogen sulfide monohydrate (0.25 g, 3.3 mmol) was added to asolution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (0.59 g, 3.0mmol) in DMF (20 ml) at room temperature and the reaction mixture wasstirred for 1 h. Potassium carbonate (1.24 g, 9 mmol) and6-bromocapronitrile (0.80 g, 4.5 mmol) were added and the reactionmixture was stirred for additionally 24 h. Water (50 ml) was added andextracted with ether. The combined ether phases were dried andevaporated to give the title compound.

B. 3-(3-(5-Cyanopentylthio)-1,2,5-thiadiazol-4-yl)-1-methylpyridiniumiodide

Methyl iodide (1 ml, 15 mmol) was added to a solution of3-(3-(5-cyanopentylthio)-1,2,5-thiadiazol-4-yl)pyridine (3 mmol) inacetone and the reaction mixture was stirred at room temperature for 20h.and evaporated.

C.3-(3-(5-Cyanopentylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (290 mg, 7.5 mmol) was added to a solution of3-(3-(5-cyanopentylthio)-1,2,5-thiadiazol-4-yl)-1-methylpyridiniumiodide (3 mmol) in ethanol (99.9%, 20 ml) and the reaction mixture wasstirred at -10° C. for 1 h. After evaporation the residue was dissolvedin water and extracted with ethyl acetate. The dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallizedas the oxalate salt from acetone to yield 410 mg. M.p.139°-140° C. Compound 68.

The following compounds were made in exactly the same manner, startingwiththe appropriate alkyl halogenide:

3-(3-(3-Chloropropylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 136°-138° C. Compound 69.

3-(3-(3-Cyanopropylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 117.5°-118° C. Compound 70.

3-(3-(3-Phenylpropylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 110°-110.5° C. Compound 71.

3-(3-(2-Phenoxyethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 125.5°-126° C. Compound 72.

3-(3-(4-Cyanobutylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 127°-127.5° C. Compound 73.

3-(3-(8-Hydroxyoctylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 112.5°-113.5° C. Compound 74.

3-(3-(4-Chlorobutylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 136°-137° C. Compound 75.

3-(3-(4,4-Bis-(4-fluorophenyl)-butylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 117.5°-118° C. Compound 76.

3-(3-(2-(1,3-Dioxolane-2-yl)-ethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 117°-118° C. Compound 77.

3-(3-(4-Cyanobenzylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 138°-140° C. Compound 78.

3-(3-(2-Phenylethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 155°-156° C. Compound 79.

3-(3-(4-Bromobenzylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 139°-140° C. Compound 80.

3-(3-(4-Methylbenzylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 162°-165° C. Compound 81.

3-(3-(4-Pyridylmethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 140°-142° C. Compound 82.

3-(3-(2-Benzoylethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 99°-100° C. Compound 83.

3-(3-(4-Oxo-4-(4-fluorophenyl)-butylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 131°-132° C. Compound

3-(3-Benzyloxycarbonylmethylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 179°-180° C. Compound 85.

3-(3-Benzylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 195°-197° C. Compound 86.

3-(3-(4,4,4-Trifluorobutylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpiperidineoxalate. M.p. 163°-165° C. Compound 87.

3-(3-(5,5,5-Trifluoropentylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 134°-136° C. Compound 88.

3-(3-(6,6,6-Trifluorohexylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 128°-129° C. Compound 89.

3-(3-Ethoxycarbonylpentylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 78°-81° C. Compound 90.

3-(3-(2,2,2-Trifluoroethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 159°-163° C. Compound 225.

3-(3-Isohexylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 131°-134° C. Compound 226.

3-(3-Ethoxycarbonylpropylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridinehydrochloride. M.p. 109°-111° C. Compound 227.

3-(3-(2-(2-Thienylthio)ethylthio))-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate.M.p. 112°-115° C. Compound 228.

3-(3-(5-Ethyl-2-thienylmethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 106°-110° C. Compound 229.

3-(3-(6-Hydroxyhexylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 108°-110° C. Compound 230.

3-(3-(3-Methyl-2-thienylmethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 184°-186° C. Compound 231.

3-(3-(2-(2-Thienylthio)propylthio))-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 193°-196° C. Compound 232.

3-(3-(4-Ethoxy-1,2,5-thiadiazol-3-ylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 173°-174° C. Compound233.

3-(3-(5-Methyl-2-thienylmethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 148°-149° C. Compound 234.

3-(3-(4-Ethylthio-1,2,5-thiadiazol-3-ylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 187°-189° C. Compound 235.

3-(3-(4-Butylthio-1,2,5-thiadiazol-3-ylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 162°-164° C. Compound 236.

3-(3-(4-Propoxy-1,2,5-thiadiazol-3-ylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 182°-183° C. Compound 237.

cis3-(3-(3-Hexenylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 101°-102° C. Compound 238.

3-(3-(1-Cyclopropylmethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 145°-146° C. Compound 239.

3-(3-(1-Ethoxycarbonylpentylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro1-methylpyridineoxalate. M.p. 94°-95° C. Compound 240.

3-(3-(5-Hexenylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 115°-116° C. Compound 241.

3-(3-Cyclopentylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 144°-145° C. Compound 242.

3-(3-(2-Methoxyethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 150°-151 ° C. Compound 243.

3-(3-(2-(2-Ethoxymethoxy)-ethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro1-methylpyridineoxalate. M.p. 117°-118° C. Compound 244.

3-(3-(4-Pentynylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 121°-122° C. Compound 245.

3-(3-Heptylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 122°-123° C. Compound 246.

3-(3-(2-Ethylbutylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 141°-142° C. Compound 247.

3-(3-Cyclohexylmethylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 153°-155° C. Compound 248.

3-(3-(7-Octenylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 115°-116° C. Compound 249.

3-(3-(3-Butenylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 140°-141° C. Compound 250.

3-(3-(4-Pentenylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 137°-138° C. Compound 251.

3-(3-(3,3,3-Trifluoropropylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 131°-135° C. Compound 252.

3-(3-(1-Oxo-1-phenylpropylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 99°-100° C. Compound 253.

3-(3-(4-Phenylthiobutylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 97°-99° C. Compound 254.

3-(3-Cyanomethylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 176°-177° C. Compound 255.

3-(3-(6-Chlorohexylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 125°-126° C. Compound 256.

3-(3-(5-Chloropentylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 106°-107° C. Compound 257.

EXAMPLE 66

A. 3-(3-(6,6,6-Trifluorohexyloxy-1,2,5-thiadiazol-4-yl)pyridine

To a mixture of sodium hydride (12.8 mmol) and 6,6,6-trifluoro-1-hexanol(3.0 g, 19.2 mmol) in tetrahydrofuran (40 ml) was added3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (1.3 g, 6.4 mmol). Themixture was refluxed for 36 h. and evaporated. After evaporation theresidue was dissolved in water then extracted with diethyl ether. Thedried organic phases were evaporated and the residue purified by columnchromatography (silica gel, eluent: ethyl acetate/hexanes) to yield 630mg (31%) of the title compound.

B.3-(3-(6,6,6-Trifluorohexyloxy-1,2,5-thiadiazol-4-yl)-1-methylpyridiniumiodide

A solution of methyl iodide (852 mg, 6.0 mmol) and3-(3-(6,6,6-trifluorohexyloxy-1,2,5-thiadiazol-4-yl)pyridine (630 mg,2.0 mmol) in acetone (25 ml) was refluxed for 7 h. The solution wasevaporatedand the residue was used directly in the next step.

C.1,2,5,6-Tetrahydro-1-methyl-3-(3-(6,6,6-trifluorohexyloxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate

Sodium borohydride (380 mg, 10 mmol) was added to a solution of3-(3-(6,6,6-trifluorohexyloxy-1,2,5-thiadiazol-4-yl)-1-methylpyridiniumiodide (2.0 mmol) in ethanol (15 ml) and the reaction mixture wasstirred at room temperature overnight. After evaporation the residue wasdissolvedin water and extracted with diethyl ether. The dried organicphases were evaporated and the residue was purified by columnchromatography (silica gel, eluent: 25% ethyl acetate in hexanes). Thetitle compound was crystallized as the oxalate salt from acetone toyield 180 mg (21%) M.p. 138°-140° C. Theoretical %C=45.17, %H=5.21,%N=9.88. Found %C=45.13, %H=5.18, %N=9.62. Compound 91.

The following compounds were made in exactly the same manner using theappropriate alkoxy derivative:

1,2,5,6-Tetrahydro-1-methyl-3-(3-(3-(2-thienyl)-1-propoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate M.p. 130°-133° C., M⁺ : 321. Compound 92.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(3-(4-methoxyphenyl)-1-propoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate M.p. 166°-167° C., M⁺ : 345. Compound 93.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-(4-methoxyphenyl)-1-ethoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate M.p. 166°-167° C., M⁺ : 331.Compound 94.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-(2-thienyl)-1-ethoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate. M.p. 145°-146° C., M⁺ : 306. Compound 95.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-(3-thienyl)-1-ethoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate. M.p. 138°-140° C., M⁺ : 306. Compound 96.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(3-hydroxy-1-propoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate. M.p. 105°-107° C., M⁺ : 256. Compound 97.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-phenyl-1-ethoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate. M.p. 146°-147° C., M⁺ : 301. Compound 98.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-thienylmethoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate. M.p. 161°-162° C., M⁺ : 294. Compound 99.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(3-hydroxy-1-hexyloxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate. M.p. 147°-148° C., M⁺ : 297. Compound 100.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(3-thienylmethoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate.M.p. 175°-176° C., M⁺ : 293. Compound 101.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(3-phenyl-1-propoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate. M.p. 136°-138° C., M⁺ : 315. Compound102.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(3-(2-pyrrolidon-1-yl)-1-propoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate. M.p. 160°-161° C., M⁺ : 322. Compound 103.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(6-acetamido-1-hexyloxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate. M.p. 114°-116° C., M⁺ : 338. Compound 104.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-acetamido-1-ethoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate. M.p. 145°-148° C., M⁺ : 283. Compound 105.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-(2-pyrrolidon-1-yl)-1-ethoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate. M.p. 170°-171° C., M⁺ : 309. Compound 106.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-propionamido-1-ethoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate. M.p. 142°-143° C., M⁺ : 296. Compound 107.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-(2-oxazolidon-3-yl)-1-ethoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate. M.p. 157°-159° C., M⁺ : 310. Compound 108.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-benzylthio-1-ethoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate. M.p. 133°-134° C., M⁺ : 347. Compound 109.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(3-(1-pyrrolidyl)-1-propoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate. M.p. 141°-142° C., M⁺ : 308. Compound 110.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-ureido-1-ethoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate. M.p. 200° C. (decompose), M⁺ : 265. Compound 111.

3-(3-(2,4-Dimethylphenylpropoxy)-1,2,5-thiadiazo1-4-yl)-1,2,5,6-tetrahydrol-methylpyridineoxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridineand1-(2,4-dimethylphenyl)-3-propanol. M.p. 159°-162° C. Compound161.

3-(3-(3,4-Dimethylphenylpropoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1methylpyridineoxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridineand1-(3,4-dimethylphenyl)-3-propanol. M.p. 119°-121° C. Compound162.

3-(3-(5-Ethyl-2-thienylmethoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridineand1-hydroxymethyl-5-ethylthiophene. M.p. 146°-148° C. Compound 163.

3-(3-(Pyrrolidin-1-yl)propoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridinedioxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridineand1-pyrrolidin-1-yl-3-propanol. M.p. 141° C. decomp. Compound 164.

3-(3-(4-Fluorophenylpropoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine and1-(4-fluorophenyl)-3-propanol. M.p. 143°-146° C. Compound 165.

3-(3-(4-Chlorophenylpropoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine and1-(4-chlorophenyl)-3-propanol. M.p. 154°-155° C. Compound 166.

3-(3-(3-Methylphenylpropoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine and1-(3methylphenyl)-3-propanol. M.p 138°-1390. Compound 167.

3-(3-(2,3-Dihydro-1-indenyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridineand1-hydroxy-2,3-dihydroindene. M.p. 157°-159° C. Compound 168.

3-(3-(4-Methylphenylpropoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine and1-(4-methylphenyl)-3-propanol. M.p. 155°-159° C. Compound 169.

3-(3-(1,2,3,4-Tetrahydro-2-naphtalyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine and1,2,3,4-tetrahydro-2-naphthol. M.p. 100°-103°. Compound 170.

3-(3-Phenylbutoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridineand-1-phenyl-4-butanol. M.p. 128°-130° C. Compound 171.

3-(3-(2-Methylphenylpropoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine and1-(2-methylphenyl)-3-propanol. M.p. 145°-148°. Compound 172.

3-(3-(2,5-Dimethylphenylpropoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine and1-(2,5-dimethylphenyl)-3-propanol. M.p. 130°-134° C. Compound 173.

3-(3-Methylthioethoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine andmethylthioethanol. M.p. 146°-147° C. Compound 174.

3-(3-Dimethylaminoethoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridinedioxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine anddimethylaminoethanol. M.p. 148°-150° C. Compound 175.

3-(3-(3,4-Dichlorophenylpropoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine and1-(3,4-dichlorophenyl)-3-propanol. M.p. 149°-151° C. Compound 176.

3-(3-Dimethylaminopropoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridinedioxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine and1-dimethylamino-3-propanol. M.p. 144°-146° C. Compound 177.

3-(3-(4-Ethylbenzyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine and1-ethyl-4hydroxymethylbenzene. M.p. 187°-190° C. Compound 178.

3-(3-(4-Methylphenylpropoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine and1-(4-methylphenyl)-3-propanol. M.p. 147°-149° C. Compound 179.

3-(3-(4-Butylbenzyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine and1-butyl-4-hydroxymethylbenzene. M.p. 187°-190° C. Compound 180.

3-(3-(1-Ethylpentyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridinefumarate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine and 3-octanol.M.p. 117°-120° C. Compound 181.

3-(3-(1-Ethylbutoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridinefumarate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine and 3-heptanol.M.p. 139°-140° C. Compound 182.

3-(3-(1-Methylpentyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridinefumarate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine and2-hexanol.M.p. 143°-144° C. Compound 183.

3-(3-(5-Hexynyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine and6-hydroxy-1-hexyne. M.p. 120°-122° C. Compound 184.

3-(3-(4-Cyclohexylbutoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine and1-cyclohexyl-4-butanol. M.p. 145°-147° C. Compound 185.

3-(3-(5-Hydroxyhexyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine and1,5-dihydroxyhexane. M.p. 128°-129° C. Compound 186.

3-(3-(5-Oxyhexyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine and5-oxo-1-hexanol. M.p. 143°-144° C. Compound 187.

3-(3-(3-Methyl-4-pentenyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine and1-hydroxy-3-methyl-4-penten. M.p. 150°-151° C. Compound 188.

3-(3-(4-Methylenecyclohexylmethyl)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine and1-hydroxymethyl-4-methylenecyclohexan. M.p. 160°-161° C.Compound 189.

3-(3-(2,3-Dimethylpentyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine and1-hydroxy-2,3-dimethylpentan. M.p. 160°-161° C. Compound 190.

3-(3-(3-Cyclohexenylmethoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine and1-hydroxymethyl-3-cyclohexen. M.p. 138°-140° C. Compound 191.

3-(3-Isobutylthioethoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine andisobutylthioethanol. M.p. 138°-140° C. Compound 192.

3-(3-Cyclopropylpropoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine and1-cyclopropyl-3-propanol. M.p. 151°-153° C. Compound 193.

3-(3-(2-Methylcyclopropylmethoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro1-methylpyridineoxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine and1-hydroxymethyl-2-methylcyclopropan. Mp 121°-122° C. Compound 194.

3-(3-Cyclopentylpropyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine and1-cyclopentyl-3-propanol. M.p. 154°-156° C. Compound 195.

3-(3-(4-Methylhexyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine and4-methyl-1hexanol. M.p. 136°-139° C. Compound 196.

3-(3-(1-Methylhexyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine and 2-heptanol.M.p. 118°-119° C. Compound 197.

3-(3-(4,4,4-Trifluorobutoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine and4,4,4trifluoro-1-butanol. M.p. 157°-160° C. Compound 198.

3-(3-(3-Methylpentyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridinefumarate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine and3-methyl-1-pentanol. M.p. 133°-134° C. Compound 199.

3-(3-(6,6,6-Trifluorohexyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine and6,6,6-trifluoro-1-hexanol. M.p. 144°-146° C. Compound 200.

3-(3-(3-Cyclobutylpropoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine and3-cyclobutyl-1-propanol. M.p. 146°-148° C. Compound 201.

3-(3-Isopropoxyethoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine andisopropoxyethanol. M.p. 142°-143° C. Compound 202.

3-(3-Isoheptyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine and isoheptanol.M.p. 150°-152° C. Compound 203.

3-(3-Isohexyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridinemaleatefrom 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine and isohexanol. M.p.72°-74° C. Compound 204.

3-(3-(2,2,2-Trifluoroethoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridinefumarate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine and2,2,2-trifluoroethanol. M.p. 131°-133° C. Compound 205.

3-(3-(2-Chlorophenylpropoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine and1-(2-chlorophenyl)-3-propanol. M.p. 147°-149° C. Compound 206.

3-(3-(3-Cyclohexylpropoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridinefumarate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine and1-cyclopropyl-3-propanol. M.p. 89°-90° C. Compound 207.

3-(3-(2-Cyclohexylethoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate from 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine and2-cyclopropylethanol. M.p. 134°-135° C. Compound 208.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-ethylsulfinyl-1-ethoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate

1,2,5,6-tetrahydro-1-methyl-3-(3-(2-ethylsulfinyl-1-ethoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate was prepared in the same manner using 2-(ethylthio)ethanol asthe starting alcohol. The intermediate3-(4-(2-ethylthio-1-ethoxy)-1,2,5-thiadiazol-3-yl)pyridine was oxidizedwith 1.1 equivalent of NalO₄ and 1 equivalent MeSO₃ H using water as thereaction solvent. After a reaction time of 3.5 h. the solution was madebasic with 2N NaOH and extracted with ethyl acetate. Thecombinedextracts were dried over MgSO₄ and evaporated under vacuum. Theresulting sulfoxide was then converted to the title compound in the samemanner described above. M.p. 171°-172° C., M⁺ : 302. Compound 112.

1,2,5,6-Tetrahydro-3-(3-(5-oxohexyl)-1,2,5-thiadiazol-4-yl)-1-methylpyridin

1,2,5,6-tetrahydro-3-(3-(5-hydroxyhexyl)-1,2,5-thiadiazol-4-yl)-1-methylpyridinewas prepared in the same manner using 1,5-hexandiol. Oxidation of thiscompound to the named ketone was carried out under conditions asfollows. To a -70° C. solution of oxalylchloride (420 μl, 4.8 mmol) in25 ml CH₂ Cl₂ was added DMSO (750 μl, 10.6 mmol) at a rate so as tomaintain the reaction temperature below -45° C. Twomin. after theaddition1,2,5,6-tetrahydro-3-(3-(5-hydroxyhexyl)-1,2,5-thiadiazol-4-yl)-1-methylpyridine(1.3 g, 4.4 mmol) in 20 ml CH₂ Cl₂ was added slowly, keeping thetemperature below -45° C. After 15 min. Et₃ N (3 ml, 21.8 mmol) wasadded and the reaction was warmed to room temperature. Brine (50 ml) wasadded and the mixture was extracted three times with 50 ml CH₂ Cl₂. Thecombined extracts were dried over Na₂ SO₄ and evaporated under vacuum.The resulting oil was chromatographed on silica gel (90% CHCl₃, 2% MeOHas eluent), affording 810 mg of an oil, which was dissolved in MeOH andtreated with oxalic acid (250 mg, 2.8 mmol). The resulting oxalate saltwas recrystallized from MeOH/EtOAc, affording 860 mg. M.p. 143°-144° C.,M⁺ : 295. Compound 113.

EXAMPLE 67

A. 3-(3-Chloro-1,2,5-oxadiazol-4-yl)pyridine

To a solution of 3-(3-amino-1,2,5-oxadiazol-4-yl)pyridine (1.0 g, 6.2mmol)in glacial acetic acid (16 ml) and concentrated hydrochloric acid(5.2 ml) was added CuCl₂ (938 mg, 7 mmol) and copper coils (100 mg) at0° C. After 10 min. a solution of sodium nitrite (483 mg, 7 mmol) inwater (3 ml) was added dropwise at 5° C. The reaction mixture wasstirred additionally 30 min. at 0° C. Aqueous sodium hydroxide (2N) wasadded to alkaline pH and the mixture extracted with ether. The etherphases were dried and evaporated to give a mixture of the titlecompounds. Separation by column chromatography (SiO₂, eluent: ethylacetate) gave the chloro compound, upper spot, in 230 mg yield.

B. 3-(3-(3-Phenylpropylthio)-1,2,5-oxadiazol-4-yl)pyridine

Sodium hydrogen sulfide monohydrate (0.74 g, 10.5 mmol) was added to asolution of 3-(3-chloro-1,2,5-oxadiazol-4-yl)pyridine (1.27, 7.0 mmol)in DMF (30 ml) at room temperature and the reaction mixture was stirredfor 1h. Potassium carbonate (2.0 g, 14.5 mmol) and1-bromo-3-phenylpropane (2.4 g, 12 mmol) were added and the reactionmixture was stirred for additionally 24 h. Water (50 ml) was added andextracted with ether. The combined ether phases were dried andevaporated. Purification by column chromatography (SiO₂, eluent: ethylacetate/methylene chloride (1:1))gave the title compound.

C. 3-(3-(3-Phenylpropylthio)-1,2,5-oxadiazol-4-yl)-1-methylpyridiniumiodide

Methyl iodide (1 ml, 15 mmol) was added to a solution of3-(3-(3-phenylpropylthio)-1,2,5-oxadiazol-4-yl)pyridine (7 mmol) inacetone and the reaction mixture was stirred at room temperature for 20h.and evaporated.

D.3-(3-(3-Phenylpropylthio)-1,2,5-oxadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (650 mg, 17 mmol) was added to a solution of3-(3-(3-phenylpropylthio)-1,2,5-oxadiazol-4-yl)-1-methylpyridinum iodide(7 mmol), in ethanol (99.9%, 20 ml) and the reaction mixture was stirredat -10° C. for 1 h. After evaporation the residue was dissolved in waterand extracted with ethyl acetate. The dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallizedas the oxalate salt from acetone and recrystallized to yield170 mg. M.p. 106°-108° C. Compound 114.

The following compound was made in exactly the same manner using theappropriate alkylhalogenide:

3-(3-(2-Phenoxyethylthio)-1,2,5-oxadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 122°-124° C. Compound 115.

3-(3-Pentylthio-1,2,5-oxadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate from 3-(3-chloro-1,2,5-oxadiazol-4-yl)pyridine, sodiumhydrogensulfide and 1-bromopentane. M.p. 123°-124° C. Compound 212.

3-(3-Hexylthio-1,2,5-oxadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate from 3-(3-chloro-1,2,5-oxadiazol-4-yl)pyridine, sodiumhydrogensulfide and 1-bromohexane. M.p. 111°-113° C. Compound 213.

3-(3-(4-Pentynylthio)-1,2,5-oxadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate from 3-(3-chloro-1,2,5-oxadiazol-4-yl)pyridine, sodiumhydrogensulfide and 1-bromo-4-pentyne. M.p. 119°-120° C. Compound 214.

EXAMPLE 681-(3-(3-Pyridyl)-1,2,5-thiadiazol-4-ylthio)-4-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-4-ylthio)butaneoxalate

To a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl)-1-methyl-1,2,5,6-tetrahydropyridine(0.43 g, 2 mmol) in DMF (30 ml) was added sodium-hydrogensulfide (0.3 g,4mmol). The reaction mixture was stirred at room temperature for 1 h.Potassium carbonate (1 g) and3-(3-(4-chlorobutylthio)-1,2,5-thiadiazol-4-yl)pyridine were added andthereaction mixture stirred at room temperature overnight. Water (200ml) was added and the water phase extracted with ether (3×100 ml). Theetherextracts were dried over magnesium sulfate and evaporated. Theresidue was purified by column chromatography (eluent: ethylacetate/methanol 9:1). The free base obtained was crystallized withoxalic acid from acetone in 0.9 g yield. (Compound 116). M.p. 127°-129°C.

EXAMPLE 691-(1-Methyltetrazol-5-ylthio)-4-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)1,2,5-thiadiazol-4-ylthio)butaneoxalate

To a solution of3-(3-(4-chlorobutylthio)-1,2,5-thiadiazol-4-yl)-1-methyl-1,2,5,6-tetrahydropyridine(0.30 g, 1 mmol) in DMF (30 ml) were added 1-methyl-5-mercaptotetrazol(0.35 g, 3 mmol) and potassium carbonate (2 g). The reaction mixture wasstirred at room temperature for 60 h. 1N hydrochloric acid was added(200 ml) and the water phase was extracted with ether (2×100 ml). Thewater phase was basified with solid potassium carbonate and extractedwith ether (3×100 ml). The ether extracts from the alkaline extractionswere combined and dried over magnesium sulfate. The ether phase wasevaporated and the residue was crystallized with oxalic acid fromacetone giving the title compound in 0.4 g yield. (Compound 117). M.p.77°-79° C.

EXAMPLE 70

The following compounds were made in exactly the same manner asdescribed in example 69 by using the reagents indicated.

1-(2-Methyl-1,3,4-thiadiazol-5-ylthio)-4-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-4-ylthio)butaneoxalate from3-(3-(4-chlorobutylthio)-1,2,5-thiadiazol-4-yl)-1-methyl-1,2,5,6-tetrahydropyridineand 2-methyl-5-mercapto-1,3,4-thiadiazole. (Compound 118). M.p.102°-104° C.

1-(2-Thiazolin-2-ylthio)-4-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-4-ylthio)butaneoxalate from3-(3-(4-chlorobutylthio)-1,2,5-thiadiazol-4-yl)-1-methyl-1,2,5,6-tetrahydropyridineand 2-thiazoline-2-thiol. (Compound 119). M.p. 116°-117° C.

1-(2-Benzoxazolylthio)-4-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-4-ylthio)butaneoxalate from3-(3-(4-chlorobutylthio)-1,2,5-thiadiazol-4-yl)-1-methyl-1,2,5,6-tetrahydropyridineand 2-mercaptobenzoxazole. (Compound 120). M.p. 156°-158° C.

1-(2-Methyl-1,3,4-thiadiazol-5-ylthio)-5-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-4-ylthio)pentaneoxalate from3-(3-(5-chloropentylthio)-1,2,5-thiadiazol-4-yl)-1-methyl-1,2,5,6-tetrahydropyridineand 2-methyl-5-mercapto-1,3,4-thiadiazole. (Compound 121). M.p. 69°-70°C.

1-(2-Benzthiazolylthio)-5-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-4-ylthio)pentaneoxalate from3-(3-(5-chloropentylthio)-1,2,5-thiadiazol-4-yl)-1-methyl-1,2,5,6-tetrahydropyridineand 2-mercaptobenzthiazole. (Compound 122). M.p. 116°-117° C.

1-(1-Methyltetrazol-5-ylthio)-5-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-4-ylthio)pentaneoxalate from3-(3-(5-chloropentylthio)-1,2,5-thiadiazol-4-yl)-1-methyl-1,2,5,6-tetrahydropyridineand 1-methyl-5-mercaptotetrazole. (Compound 123). M.p. 96°-97° C.

1-(2-Methyl-1,3,4-thiadiazol-5-ylthio)-6-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-4-ylthio)hexaneoxalate from3-(3-(6-chlorohexylthio)-1,2,5-thiadiazol-4-yl)-1-methyl-1,2,5,6-tetrahydropyridineand 2-methyl-5-mercapto-1,3,4-thiadiazole. (Compound 124). M.p. 85°-86°C.

1-(1-Methyltetrazol-5-ylthio)-6-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-4-ylthio)hexaneoxalate from3-(3-(6-chlorohexylthio)-1,2,5-thiadiazol-4-yl)-1-methyl-1,2,5,6-tetrahydropyridineand 1-methyl-5-mercaptotetrazole. (Compound 125). M.p. 65°-66° C.

1-(2-Thiazolin-2-ylthio)-6-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-4-ylthio)hexaneoxalate from3-(3-(6-chlorohexylthio)-1,2,5-thiadiazol-4-yl)-1-methyl-1,2,5,6-tetrahydropyridineand 2-thiazoline-2-thiol. (Compound 126). M.p. 61°-62° C.

EXAMPLE 713-(3-Methylsulfonyl-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate hemiacetone

A solution of3-(3-methylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate(0.25 g, 0.0079 mol) in H₂ O (10 ml) was cooled in an ice-water bath asa solution of oxone (0.7 g, 0.00114 mol) in H₂ O (5ml) was addeddropwise. Cooling was removed and after 5 h excess NaHSO₃ was added. Thesolution was cooled in an ice-water bath, the solution made basic, andthe mixture extracted with CH₂ Cl₂ (3×25 ml). The extracts were dried,the solvent evaporated, and the residue purified by radialchromatography (5% EtOH-0.5% NH₄ OH--CHCl₃) to give a white crystallinesolid (0.2 g). The oxalate salt recrystallized from acetone to givecolorless crystals. M.p. 96°-97.5° C. (Compound 127). Analysis and NMRconfirmed thatthe salt contained 0.5 mol of acetone. Analysis C₉ H₁₃,N₃O₂ S--C₂ H₂ O₄ -0.5 C₃ H₆ O, C,H,N;

Theory C, 39.68; H, 4.79; N, 11.10; Found C, 39.52; H, 4.85; N, 11.19.

3-(3-2-(1-Pyrrolidinyl)ethoxy!-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridinedioxalate

A suspension of NaH (0.0075 mol) in THF (25 ml) was treated with2-hydroxyethylpyrrolidine (1 ml, 0.0086 mol) and after 30 min. the freebase of (Compound 127) (0.6 g, 0.0023 mol), was added. After anotherhour,H₂ O (2 ml) was added and the solvent evaporated. The residue wassuspended in H₂ O and extracted with CH₂ Cl₂ (3×25 ml). The extractswere dried, the solvent evaporated, and the residue purified by radialchromatography (20% EtOH-2% NH₄ OH--CHCl₃) togive a straw colored liquid(0.4 g). The dioxalate salt recrystallized fromEtOH to give a whitesolid. M.p. 186°-188° C. (Compound 128).

Analysis C₁₄ H₂₂,N₄ OS-2C₂ H₂ O₄, C,H,N; Theory C, 45.57; H, 5.52; N,11.81; Found C, 45.53; H, 5.50; N, 11.61.

EXAMPLE 723-(3-(3-(5-Methyl-2-thienyl)-1-propoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium hydride (10.2 mmol) was added to a solution of3-(5-methyl-2-thienyl)-1-propanol (4.0 g, 25.5 mmol) in THF (40 ml). Themixture was stirred for 1 h at room temperature, whereupon a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (1.0 g, 5.1 mmol) in THF (10ml) was added dropwise to the reaction mixture. After stirring overnightat room temperature, the reaction was quenched with water then extractedwith diethyl ether. The organic phase was dried over NaCl/Na₂ SO₄ thenevaporated to yield crude3-(3-(5-methyl-2-thienyl)propoxy-1,2,5-thiadiazol-4-yl)pyridine. Asolution of3-(3-(5-methyl-2-thienyl)propoxy-1,2,5-thiadiazol-4-yl)pyridine (1.0 g,3.2 mmol) and iodomethane (2.3 g, 16.0 mmol) in 60 ml of acetone wasrefluxed overnight. The solution was evaporated to yield 1.5 g of thequaternized product. Sodium borohydride (0.6 g, 16.0 mmol) was carefullyadded to a solution of the quaternized product (1.5 g) in ethanol (30ml).The reaction was evaporated and the resulting residue was taken upin waterand extracted with methylene chloride (3×100 ml). The organicphase was dried over NaCl/Na₂ SO₄ then evaporated. The residue waspurified by radial chromatography eluting with 0.5% NH₄ OH/5.0% EtOH inCHCl₃. The oxalate salt was made to yield 337 mg of the title compound.M.p. 134°-137° C. (Compound 129).

The following compounds were made in the same manner as described aboveusing the indicated alcohol instead of3-(5-methyl-2-thienyl)-1-propanol:

3-(3-((5-Propyl-2-thienyl)methoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate (Compound 130) from (5-propyl-2-thienyl)-methanol. M.p.134°-135° C.

3-(3-(3-(5-Pentyl-2-thienyl)-1-propoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate (Compound 131) from 3-(5-pentyl-2-thienyl)-1-propanol. M.p.138°-140° C.

3-(3-(3-(2-Thienylthio)-1-propoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate (Compound 132) from 3-(2-thienylthio)-1-propanol. M.p. 102°-110°C.

EXAMPLE 733-(3-(3-(2-Thienyl)-1-propylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

A solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (2.0 g, 10.1mmol)in DMF (10 ml) was cooled to 5° C. whereupon potassium carbonate(2.8 g, 20.2 mmol) and sodium hydrosulfide monohydrate (1.5 g, 20.2mmol) were added to the reaction. Stirred for 1 h then potassiumcarbonate (1.4 g, 10.1 mmol) and a solution of3-(2-thienyl)-1-chloropropane (1.8 g, 11.2mmol) in DMF (5 ml) were addedto the reaction and stirred for 1 h at room temperature. The reactionwas quenched with water then extracted with methylene chloride (3×75ml). The organic phase was dried over NaCl/Na₂ SO₄ then evaporated. Theresidue was purified by flash chromatography eluting with 1:1 ethylacetate/hexanes to yield 1.0 g of3-(3-(3-(2-thienyl)-1-propylthio)-1,2,5-thiadiazol-4-yl)pyridine.Quaternization and reduction was done as described in example 72.(Compound 133). M.p. 98°-100° C.

The following compounds were made in exactly the same manner asdescribed above using the indicated alkylhalogenide:

3-(3-(2-Thienylmethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate (Compound 134) using (2-thienyl)-chloromethane. M.p. 131°-135°C.

3-(3-(3-(2-Oxazolidinon-3-yl)-1-propylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate (Compound 135) using 3-(2-oxazolidinon-3-yl)-1-chloropropane.M.p. 104°-109° C.

3-(3-(3-(2-Thiazolidinon-3-yl)-1-propylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate (Compound 136) using 3-(2-thiazolidinon-3-yl)-1-chloropropane.M.p. 75°-81° C.

3-(3-(5-Pentyl-2-thienyl)methylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate (Compound 137) using (5-pentyl-2-thienyl)chloromethane. M.p.143°-146° C.

(R)-(+)3-(3-(3-(4-Benzyl-2-oxazolidinon-3-yl)-1-propylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate (Compound 138) using (R)3-(4-benzyl-2-oxazolidinon-3-yl)-1-chloropropane. M.p. 124°-133° C.

(S)-(-)3-(3-(3-(4-Benzyl-2-oxazolidinon-3-yl)-1-propylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate (Compound 139) using(S)-3-(4-benzyl-2-oxazolidinon-3-yl)-1-chloropropane. M.p. 132°-135° C.

(4R,5S)-3-(3-(3-(4-Methyl-5-phenyl-2-oxazolidinon-3-yl)-1-propylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate (Compound 140) using(4R,5S)-3-(4-methyl-5-phenyl-2-oxazolidinon-3-yl)-1-chloropropane. M.p.102°-106° C.

(S)-3-(3-(3-(4-Isopropyl-2-oxazolidinon-3-yl)-1-propylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate (Compound 141) using(S)-3-(4-isopropyl-2-oxazolidinon-3-yl)-1-chloropropane. M.p. 75°-79° C.

(S)-3-(3-(3-(4-Ethyl-2-oxazolidinon-3-yl)-1-propylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate (Compound 142) using(S)-3-(4-ethyl-2-oxazolidinon-3-yl)-1-chloropropane. M.p. 69°-71° C.

(S)-3-(3-(3-(4-(2-Butyl)-2-oxazolidinon-3-yl)-1-propylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate (Compound 143) using(S)-3-(4-(2-butyl)-2-oxazolidinon-3-yl)-1-chloropropane. M.p. 77°-80° C.

3-(3-(3-(4-Propyl-2-oxazolidinon-3-yl)-1-propylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate (Compound 144) using3-(4-propyl-2-oxazolidinon-3-yl)-1-chloropropane. M.p. 65°-68° C.

EXAMPLE 74

A. 4-Methyl-1-(phenoxycarbonyl)-1,4-dihydropyridine

In a dry 500 ml three neck flask under nitrogen, a solution of cuprousiodide (0.28 g, 1.5 mmol) and dimethyl sulfide (8 ml) in 30 ml of dryTHF was stirred at room temperature for 10 minutes. Pyridine (2.43 ml,30 mmol) in 120 ml of dry THF was added to the reaction, then cooled to-25° C. Phenylchloroformate (3.9 ml, 30 mmol) in 10 ml dry THF was addedto the reaction via an addition funnel (a thick brown precipitate formedimmediately upon addition). The mixture was stirred for 15minutes.Methyl magnesium chloride (10 ml, 30 mmol) was added to themixture via syringe whereupon the brown precipitate dissolved. Thereaction was stirred at -25° C. for 20 minutes then stirred at roomtemperature for 20 minutes. 20% NH₄ Cl.sub.(aq) (70 ml) was added to thereaction. The mixture was then extracted with 150 ml diethyl ether. Theorganic extract was then washed with 40 ml portions of 20% NH₄Cl.sub.(aq) /NH₄ OH (1:1), water, 10% HCl.sub.(aq), water, and brine.Theorganic layer was then dried over NaCl/Na₂ SO₄, filtered,andconcentrated to yield 5.9 g of a yellow oil. Kugelrohr distillation(bp. 150°-170° C., 1 mmHg) to yield 4.9 g (77%) of the desired compound(A).

B. 3-Formyl-4-methyl-1-(phenoxycarbonyl)-1,4-dihydropyridine

To a dry 50 ml flask under nitrogen, DMF (7.44 ml, 97 mmol) in 10 ml ofdichloromethane was cooled to 0° C. Phosphorus oxychloride (4.5 ml,48mmol) was slowly added to the solution. The solution was stirred atroomtemperature for 30 minutes. (A) (4.7 g, 22 mmol) in 40 ml ofdichloromethane was stirred in a 100 ml two neck flask under nitrogen at0° C. The DMF/Phosphorus oxychloride solution was transferred toanaddition funnel via cannula then slowly added to the(A)/dichloromethane solution. The ice bath was then removed, and thereaction was stirred at room temperature for 20 hours. The reaction wascooled to 0° C. whereupon a solution of potassium acetate (15 g) in 50ml of water was carefully added via the addition funnel. The mixture wasthen allowed to reflux for 20 minutes. The methylene chloride layer wasseparated then extracted once more with 100 ml methylene chloride. Theorganic phases were combined then washed with 40 ml portions of water,K₂ CO₃(aq), water and brine, then dried over NaCl/Na₂ SO₄. Theorganicswere concentrated on a rotary evaporator to yield 4 g of a brown oil.Purified by flash chromatography over silica gel eluting with ethylacetate/hexane. Yield 2.0 g (37%) of the desired compound (B).

C. 4-Methyl-3-pyridinecarboxaldehyde

Methanol (85 ml), triethylamine (1.4 g), and (B) (5.0 g, 20.6 mmol) wereplaced in a 250 ml flask over nitrogen. The solution was refluxed for 3hours. The reaction was then concentrated and 5% Pd/C (0.5 g) andtoluene (85 ml) were added to the flask. This mixture was refluxed for 2hours, then cooled to room temperature. The 5% Pd/C was removed byfiltration andthe filtrate was concentrated.

The resulting oil was purified by flash chromatography over silica geleluting with ethyl acetate/hexane. The yield of (C) was 1.3 g (47%).

D. Alpha-amino-alpha(3-(4-methylpyridyl))acetonitrile

Dissolved potassium cyanide (7.3 g, 112.6 mmol) and ammonium chloride(6.0 g, 112.6 mmol) in water (150 ml) in a 250 ml flask under nitrogen.(C) (10.9 g, 90.1 mmol) was added to the reaction which was stirred atroom temperature overnight. The reaction mixture was extracted withethyl acetate (3×300 ml). The organic extracts were combined, dried overNaCl/Na₂ SO₄, then concentrated to yield 11 g of a brown oil (D). Useddirectly in the next step.

E. 3-(3-Chloro-1,2,5-thiadiazol-4-yl)-4-methylpyridine

Sulfurmonochloride (73.5 mmol, 5.9 ml) in DMF (90 ml) was placed in a250 ml flask under nitrogen and cooled to -25° C. (D) (3.6 g, 24.5 mmol)in DMF (10 ml) was added to the reaction via an addition funnel.Thereaction was allowed to stir overnight. After warming to roomtemperature, water (30 ml) and diethyl ether (60 ml) were added to thereaction and theether layer was separated, then discarded. The reactionwas then basified with 50% NaOH.sub.(aq), then extracted with diethylether (4×90 ml).The organic extracts were combined, dried over NaCl/Na₂SO₄, and concentrated to yield a brown oil. The oil was purified byflash chromatography over 100 g silica gel, eluting with 0.05% NH₄OH/0.5% ethanol in chloroform. Yield of (E) was 2 g (38%).

F. 3-(3-Methoxy-1,2,5-thiadiazol-4-yl)-4-methylpyridine

A solution of sodium (0.32 g, 14 mmol) in methanol (10 ml) was preparedin a 25 ml flask under nitrogen. (E) (0.6 g, 2.8 mmol) was added to thereaction and was heated at 50° C. for 3 hours, then stirred overnight atroom temperature. Concentrated on the rotary evaporator then dissolvedthe resulting solid in 1N HCl.sub.(aq) and washed with diethyl ether.The aqueous layer was basified with 5N NaOH.sub.(aq), then extractedwith methylene chloride (4×50 ml). The combined organic extracts weredried over NaCl/Na₂ SO₄ and concentrated to yield 344 mg of an oil (F)(60%).

G. 3-(3-Methoxy-1,2,5-thiadiazol-4-yl)-4-methylpyridinium iodide

A mixture of (F) (335 mg, 1.6 mmol), iodomethane (1.14 g, 8.0 mmol), andacetone (100 ml) was stirred in a 250 ml flask under nitrogen overnightatroom temperature. Concentrated the reaction on the rotary evaporatorto yield 500 mg of a yellow solid (G). Used directly in next step.

H.1,2,5,6-Tetrahydro-3-(3-methoxy-1,2,5-thiadiazol-4-yl)-1,4-dimethylpyridinefumarate

Sodium borohydride (300 mg, 8.0 mmol) was added to a solution of (G)(1.6 mmol) and ethanol (15 ml) in a 50 ml flask under nitrogen. Thereaction was allowed to stir overnight at room temperature. The reactionwas concentrated on the rotary evaporator. Dissolved the resulting solidin 1NHCl.sub.(aq) (75 ml), then washing with diethyl ether. The aqueouslayer was basified, then extracted with methylene chloride (4×75 ml).The combined organic extracts were dried over NaCl/Na₂ SO₄, andconcentrated to yield an oil which was purified by flash chromatography(silica gel eluting with NH₄ OH/ethanol in chloroform). Yield was 91 mg.Isolated as fumarate salt, 130.4 mg. M.p. 99°-105° C. Analysis calc. forC₁₄ H₁₉ N₃ O₅ S. C: 49.26; H: 5.61;N: 12.31. Found C: 49.11; H: 5.53; N:12.03. Compound 145.

EXAMPLE 75

The following compound was made in exactly the same manner as describedin example 74F through H using hexanol instead of methanol:

3-(3-Hexyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1,4-dimethylpyridineoxalate. M.p. 109°-111° C. Analysis calc. for C₁₇ H₂₇ N₃ O₅ S. C: 52.97;H: 7.06; N: 10.70. Found C: 53.17; H: 6.88; N: 10.98. Compound 146.

EXAMPLE 76

A. Alpha-amino-alpha-(6-methyl-3-pyridinyl)acetonitrile

To a solution of potassium cyanide (6.96 g, 107 mmol) and ammoniumchloride(5.72 g, 107 mmol) in water (5 ml) was added6-methyl-3-pyridin-carboxaldehyde (8.68 g, 71.5 mmol) and the reactionmixture was stirred at room temperature for 18 h. The reaction mixturewasbasified with 50% NaOH and extracted with ethyl acetate. The organicphase was dried (MgSO₄) and evaporated to give the crude desired productin7 g yield. The product was used without further purification.

B. 3-(3-Chloro-1,2,5-thiadiazol-4-yl)-6-methylpyridine

A solution of sulphurmonochloride (11.7 ml, 142 mmol) in DMF (50 ml) wasslowly added to a solution ofalpha-amino-alpha-(6-methyl-3-pyridinyl)acetonitrile (7 g, 47 mmol) atroom temperature. The reaction mixture was stirred for 18 h andthereafterbasified with 50% NaOH and extracted with ether. The etherphases were dried (MgSO₄) and evaporated. The residue was purified bycolumn chromatography (eluent, EtOAc:CH₂ Cl₂ (1:1)) to give the wantedproduct in 5.30 g (54%) yield.

C. 3-(3-Hexylthio-1,2,5-thiadiazol-4-yl)-6-methylpyridine

Sodium hydrogen sulfide monohydrate (0.33 g, 4.4 mmol) was added to asolution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)-6-methylpyridine (0.85 g,4mmol) in DMF (20 ml) at room temperature and the reaction mixture wasstirred for 1 h. Potassium carbonate (1.65 g, 12 mmol) and1-hexylbromide (0.99 g, 6 mmol) were added and the reaction mixture wasstirred for additionally 24 h. 1N HCl was added and the reaction mixturewas extractedonce with ether. The aqueous phase was basified with 50%NaOH and extractedwith ether. The ether phases were dried and evaporatedto give crude title compound.

D. 3-(3-Hexylthio-1,2,5-thiadiazol-4-yl)-1,6-dimethylpyridinium iodide

Methyl iodide (1 ml, 15 mmol) was added to a solution of3-(3-hexylthio-1,2,5-thiadiazol-4-yl)-6-methylpyridine (4 mmol) inacetone(5 ml) and the reaction mixture was stirred at room temperaturefor 20 h. Evaporation of the reaction mixture gave the crude product,which was usedwithout further purification.

E.3-(3-Hexylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1,6-dimethylpyridineoxalate

Under nitrogen, sodium borohydride (380 mg, 10 mmol) was added to asolution of 3-(3-hexylthio-1,2,5-thiadiazol-4-yl)-1,6-dimethylpyridiniumiodide (4 mmol) in ethanol (99.9%, 20 ml) at -10° C. The reactionmixture was stirred at -10° C. for 1 h. After evaporation the residuewas dissolved in water and extracted with ethyl acetate. Thedriedorganic phases were evaporated and the residue purified by columnchromatography (eluent: EtOAc:MeOH (4:1)). The title compound wascrystallized as the oxalate salt from acetone. Recrystallization fromacetone gave the wanted product in 700 mg yield. M.p. 127°-128° C.(Compound 147).

EXAMPLE 77

The following compounds were made in the same manner as described inexample 76C through E using the appropriate alkylbromide instead of1-hexylbromide:

3-(3-Pentylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1,6-dimethylpyridineoxalate. M.p. 112°-113° C. (Compound 148).

3-(3-(4-Cyanobenzylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1,6-dimethylpyridineoxalate. M.p. 74°-76° C. (Compound 149).

3-(3-(4-Cyanobutylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1,6-dimethylpyridineoxalate. M.p. 99°-101° C. (Compound 150).

3-(3-Butylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1,6-dimethylpyridineoxalate. M.p. 119°-120° C. (Compound 151).

3-(3-Ethylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1,6-dimethylpyridineoxalate. M.p. 154°-155° C. (Compound 152).

3-(3-(4-Pentynylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1,6-dimethylpyridineoxalate. M.p. 111°-113° C. (Compound 153).

3-(3-(3-Phenylpropylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1,6-dimethylpyridineoxalate. M.p. 125°-126° C. (Compound 154).

EXAMPLE 78

A. 3-(3-Hexyloxy-1,2,5-thiadiazol-4-yl)-6-methylpyridine

Sodium hydride (0.72 g, 15 mmol) was dissolved in dry THF (20 ml) and1-hexanol (1.53 g, 15 mmol) and a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl)-6-methylpyridine (1.06 g, 5 mmol) indry THF (15 ml) was added. The reaction mixture was stirred for 2 h.Afteraddition of water the mixture was extracted with ether, and theether phasewas dried and evaporated. The residue consisted of the crudetitle compound, which was used without further purification.

B.3-(3-Hexyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1,6-dimethylpyridineoxalate

M.p. 99°-100° C. (Compound 155) was made in the same manner as describedin example 76D through E.

EXAMPLE 79

The following compounds were prepared in the same manner as described inexample 78 using the appropriate alcohol instead of 1-hexanol:

3-(3-Pentyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1,6-dimethylpyridineoxalate. M.p. 122°-123° C. (Compound 156).

3-(3-Butoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1,6-dimethylpyridineoxalate. M.p. 133°-134° C. (Compound 157).

3-(3-(4-Pentenyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1,6-dimethylpyridineoxalate. M.p. 133°-134° C. (Compound 158).

3-(3-(3-Hexynyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1,6-dimethylpyridineoxalate. M.p. 126°-128° C. (Compound 159).

3-(3-Ethoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1,6-dimethylpyridineoxalate. M.p. 128°-129° C. (Compound 160).

EXAMPLE 803-(3-(3-Carboxypropylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine

A solution of3-(3-(3-carboxypropylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridinehydrochloride (0.70 g, 2 mmol) in concentrated hydrochloric acid (10 ml)was heated at reflux for 6 hours. The reaction mixture was evaporated atreduced pressure. The residue was dissolved in water and neutralizedwith a sodiumhydroxide solution giving the title compound in 80 % yield.M.p. 99°-101° C. Compound 258.

In exactly the same manner the following compounds were prepared:

3-(3-(3-Carboxypropoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine.M.p. 113°-116° C. Compound 259.

3-(3-(5-Carboxypentylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine.M.p. 110°-112° C. Compound 260.

EXAMPLE 813-(3-(5-Mercaptopentylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

To a solution of3-(3-(5-chloropentylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine(0.31 g, 1 mmol) in dimethylformamide (5 ml) was added sodiumhydrogensulfide (0.35 g, 5 mmol) and the mixture was stirred at roomtemperature for 48 hours. Water was added and the free base extractedwithether. The free base was crystallized as the oxalate salt fromacetone. Yield 50%. M.p. 106°-107° C. Compound 261.

In exactly the same manner the following compounds were prepared:

3-(3-(6-Mercaptohexylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 105°-106° C. Compound 262.

3-(3-(4-Mercaptobutylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 142°-144° C. Compound 263.

I claim:
 1. A method of treating a gastrointestinal hypermotilitydisorder in a subject in need thereof comprising administering to saidsubject an effective amount of a compound of formula I ##STR6## whereinZ¹ is oxygen or sulphur;R is hydrogen; halogen; amino; --NHCO--R² ; C₃₋₇-cycloalkyl; C₄₋₁₀ -(cycloalkylalkyl); --Z² --C₃₋₇ -cycloalkyloptionally substituted with C₁₋₆ -alkyl; --Z² --C₄₋₁₀-(cycloalkylalkyl); --Z² --C₄₋₁₀ -(cycloalkenylalkyl); --Z² --C₄₋₁₀-(methylenecycloalkylakyl); --NH--R² ; --NR² R³ ; --NH--OR² ; phenyl;phenoxy; benzoyl; benzyloxycarbonyl; tetrahydronaphthyl; indenyl; R² ;--Z² R² ; --SOR² ; --SO₂ R² ; --Z² R² --Z³ --R³ ; --Z² --R² --Z³ --R³--Z⁴ --R⁴ ; --Z² --R² --CO--R³ ; --Z² --R² --CO₂ --R³ ; --Z² --R² --O₂C--R³ ; --Z² --R² --CONH--R³ ; or --Z² --R² --NHCOR³ ; wherein Z², Z³and Z⁴ independently are oxygen or sulphur, and R², R³ and R⁴independently are straight or branched C₁₋₅ -alkyl, straight or branchedC₂₋₁₅ -alkenyl, straight or branched C₂₋₁₅ -alkynyl, each of which isoptionally substituted with halogen(s), --OH, --CN, --CF₃, --SH, --COOH,--NH--R², --NR² R³, C₁₋₆ -alkyl ester, one or two phenyl, phenoxy,benzoyl or benzyloxycarbonyl wherein each aromatic group is optionallysubstituted with one or two halogen, --CN, C₁₋₄ -alkyl or C₁₋₄ -alkoxy;R⁵ and R⁶ may be present at any appropriate position and independentlyare hydrogen, straight or branched C₁₋₅ -alkyl, straight or branchedC₂₋₅ -alkenyl, straight or branched C₂₋₅ -alkynyl, straight or branchedC₁₋₁₀ -alkoxy, --OH, halogen, --NH₂, carboxy, or straight or branchedC₁₋₅ -alkyl substituted with --OH; and R¹ is hydrogen, straight orbranched C₁₋₅ -alkyl, straight or branched C₂₋₅ -alkenyl or straight orbranched C₂₋₅ -alkynyl; ora pharmaceutically acceptable salt thereof. 2.The method according to claim 1, wherein Z¹ is sulphur.
 3. The methodaccording to claim 2, wherein R¹ is hydrogen or straight or branchedC₁₋₅ -alkyl, R⁵ and R⁶ independently are hydrogen, methyl, methoxy,hydroxy, halogen or amino.
 4. The method according to claim 2, whereinR¹ is hydrogen or methyl, R⁵ and R⁶ are hydrogen, R is --Z² R² whereinZ² is oxygen or sulphur and R² is straight or branched C₁₋₅ -alkyl. 5.The method according to claim 2, wherein R¹ is hydrogen or methyl, R⁵and R⁶ are hydrogen, R is --Z² R² wherein Z² is oxygen or sulphur and R²is straight or branched C₁₋₅ -alkyl substituted with halogen(s) or--CF₃.
 6. The method according to claim 1, wherein the compoundis:1,2,5,6-Tetrahydro-3-(3-methoxy-1,2,5-thiadiazol-4-yl)-1-methylpyridine;3-(3-Ethoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;1,2,5,6-Tetrahydro-1-methyl-3-(3-propoxy-1,2,5-thiadiazol-4-yl)pyridine;3-(3-Butoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;1,2,5,6-Tetrahydro-3-(3-isopropoxy-1,2,5-thiadiazol-4-yl)-1-methylpyridine;1,2,5,6-Tetrahydro-1-methyl-3-(3-pentyloxy-1,2,5-thiadiazol-4-yl)pyridine;1,2,5,6-Tetrahydro-3-(3-isobutoxy-1,2,5-thiadiazol-4-yl)-1-methylpyridine;1,2,5,6-Tetrahydro-3-(3-isopentyloxy-1,2,5-thiadiazol-4-yl)-1-methylpyridine;3-(3-Hexyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(3-Butenyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(2-Butynyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;1,2,5,6-Tetrahydro-1-methyl-3-(3-propargyloxy-1,2,5-thiadiazol-4-yl)pyridine;3-(3-Butoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydropyridine;3-(3-Ethoxy-1,2,5-thiadiazol-4-yl)-1-ethyl-1,2,5,6-tetrahydropyridine;3-(3-Heptyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(3-Pentynyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(4-Pentenyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(2-Propenyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Octyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(3-Hexynyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(3-Methyl-2-butenyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(3-Butenyl-2-oxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(4-Hexenyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;trans-3-(3-(3-Hexenyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;cis-3-(3-(2-Pentenyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;cis-3-(3-(2-Hexenyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(5-Hexenyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;cis-3-(3-(3-Hexenyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;trans-3-(3-(2-Hexenyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;1,2,5,6-Tetrahydro-3-(3-hexyloxy-1,2,5-thiadiazol-4-yl)pyridine;1,2,5,6-Tetrahydro-3-(3-methoxy-1,2,5-thiadiazol-4-yl)-1,4-dimethylpyridine;3-(3-Hexyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1,4-dimethylpyridine;3-(3-Hexyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1,6-dimethylpyridine;3-(3-Pentyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1,6-dimethylpyridine;3-(3-Butoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1,6-dimethylpyridine;3-(3-(4-Pentenyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1,6-dimethylpyridine;3-(3-(3-Hexynyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1,6-dimethylpyridine;3-(3-Ethoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1,6-dimethylpyridine;3-(3-(1-Ethylpentyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(1-Ethylbutoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(1-Methylpentyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(5-Hexynyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(3-Methyl-4-pentenyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(2,3-Dimethylpentyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(4-Methylhexyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(1-Methylhexyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(3-Methylpentyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Isoheptyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Isohexyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Hexyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-ethylpyridine;3-(3-Ethoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydropyridine; orapharmaceutically acceptable salt thereof.
 7. The method according toclaim 1, wherein the compoundis:3-(3-Cyclopropylmethoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;1,2,5,6-Tetrahydro-3-(3-methoxyethoxy-1,2,5-thiadiazol-4-yl)-1-methylpyridine;3-(3-(2-(2-Methoxyethoxy)ethoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(3-Ethoxy-1-propoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(2-Ethoxyethoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(2-Butoxyethoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(2-(2-Butoxyethoxy)ethoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(2-(2-Ethoxyethoxy)ethoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;1,2,5,6-Tetrahydro-1-methyl-3-(3-(6,6,6-trifluorohexyloxy)-1,2,5-thiadiazol-4-yl)pyridine;1,2,5,6-Tetrahydro-1-methyl-3-(3-(3-(4-methoxyphenyl)-1-propoxy)-1,2,5-thiadiazol-4-yl)pyridine;1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-(4-methoxyphenyl)-1-ethoxy)-1,2,5-thiadiazol-4-yl)pyridine; 1.2,5,6-Tetrahydro-1-methyl-3-(3-(3-hydroxy-1-propoxy)-1,2,5-thiadiazol-4-yl)pyridine;1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-phenyl-1-ethoxy)-1,2,5-thiadiazol-4-yl)pyridine;1,2,5,6-Tetrahydro-1-methyl-3-(3-(3-hydroxy-1-hexyloxy)-1,2,5-thiadiazol-4-yl)pyridine;1,2,5,6-Tetrahydro-1-methyl-3-(3-(3-phenyl-1-propoxy)-1,2,5-thiadiazol-4-yl)pyridine;1,2,5,6-Tetrahydro-1-methyl-3-(3-(6-acetamido-1-hexyloxy)-1,2,5-thiadiazol-4-yl)pyridine;1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-acetamido-1-ethoxy)-1,2,5-thiadiazol-4-yl)pyridine;1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-propionamido-1-ethoxy)-1,2,5-thiadiazol-4-yl)pyridine;1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-benzylthio-1-ethoxy)-1,2,5-thiadiazol-4-yl)pyridine;1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-ureido-1-ethoxy)-1,2,5-thiadiazol-4-yl)pyridine;1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-ethylsulfinyl-1-ethoxy)-1,2,5-thiadiazol-4-yl)pyridine;3-(3-(2,4-Dimethylphenylpropoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(3,4-Dimethylphenylpropoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(4-Fluorophenylpropoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(4-Chlorophenylpropoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(3-Methylphenylpropoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(4-Methylphenylpropoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Phenylbutoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(2-Methylphenylpropoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(2,5-Dimethylphenylpropoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Methylthioethoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Dimethylaminoethoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(3,4-Dichlorophenylpropoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Dimethylaminopropoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(4-Methylphenylpropoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(4-Cyclohexylbutoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(5-Hydroxyhexyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(5-Oxyhexyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(3-Cyclohexenylmethoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Isobutylthioethoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Cyclopropylpropoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(2-Methylcyclopropylmethoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Cyclopentylpropyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(4,4,4-Trifluorobutoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(6,6,6-Trifluorohexyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(3-Cyclobutylpropoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Isopropoxyethoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(2,2,2-Trifluoroethoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(2-Chlorophenylpropoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(3-Cyclohexylpropoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(2-Cyclohexylethoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(2,2,2-Trifluoroethoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydropyridine;3-(3-(3-Carboxypropoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;ora pharmaceutically acceptable salt thereof.
 8. The method according toclaim 1, wherein the compoundis:3-(3-Benzyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(2,3-Dihydro-1-indenyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(1,2,3,4-Tetrahydro-2-naphthalyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(4-Ethylbenzyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(4-Butylbenzyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;ora pharmaceutically acceptable salt thereof.
 9. The method according toclaim 1, wherein the compoundis:3-(3-Propylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Butylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Methylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Octylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Ethylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Pentylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Hexylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Hexylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1,6-dimethylpyridine;3-(3-Pentylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1,6-dimethylpyridine;3-(3-Butylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1,6-dimethylpyridine;3-(3-Ethylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1,6-dimethylpyridine;3-(3-(4-Pentynylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1,6-dimethylpyridine;3-(3-Hexylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-ethylpyridine;3-(3-Ethylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-ethylpyridine;3-(3-Ethylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydropyridine;3-(3-Propylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydropyridine;3-(3-Butylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydropyridine;3-(3-Pentylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydropyridine;3-(3-Hexylthio-1,2,5-thiadiazol-4-yl-1,2,5,6-tetrahydropyridine;3-(3-(4-Pentynylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydropyridine;3-(3-Isohexylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;cis3-(3-(3-Hexenylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(5-Hexenylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Cyclopentylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(4-Pentynylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Heptylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(7-Octenylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(3-Butenylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(4-Pentenylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;ora pharmaceutically acceptable salt thereof.
 10. The method according toclaim 1, wherein the compoundis:3-(3-(5-Cyanopentylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(3-Chloropropylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(3-Cyanopropylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(3-Phenylpropylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(2-Phenoxyethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(4-Cyanobutylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(8-Hydroxyoctylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(4-Chlorobutylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(4,4-Bis-(4-fluorophenyl)-butylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(2-Phenylethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(2-Benzoylethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(4-Oxo-4-(4-fluorophenyl)-butylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Benzyloxycarbonylmethylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(4,4,4-Trifluorobutylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(5,5,5-Trifluoropentylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(6,6,6-Trifluorohexylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Ethoxycarbonylpentylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(4-Cyanobutylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1,6-dimethylpyridine;3-(3-(3-Phenylpropylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1,6-dimethylpyridine;3-(3-(2,2,2-Trifluoroethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydropyridine;3-(3-(2-Phenoxyethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydropyridine;3-(3-(2,2,2-Trifluoroethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Ethoxycarbonylpropylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(6-Hydroxyhexylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(1-Cyclopropylmethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(1-Ethoxycarbonylpentylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(2-Methoxyethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(2-(2-Ethoxymethoxy)-ethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(2-Ethylbutylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Cyclohexylmethylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(3,3,3-Trifluoropropylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(1-Oxo-1-phenylpropylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(4-Phenylthiobutylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Cyanomethylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(6-Chlorohexylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(5-Chloropentylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(3-Carboxypropylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(5-Carboxypentylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(5-Mercaptopentylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(6-Mercaptohexylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(4-Mercaptobutylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;ora pharmaceutically acceptable salt thereof.
 11. The method accordingto claim 1, wherein the compoundis:3-(3-(4-Cyanobenzylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(4-Bromobenzylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(4-Methylbenzylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Benzylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(4-Cyanobenzylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1,6-dimethylpyridine;ora pharmaceutically acceptable salt thereof.
 12. The method accordingto claim 1, wherein the compoundis:3-(3-Chloro-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Chloro-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydropyridine;3-(3-Chloro-1,2,5-thiadiazol-4-yl)-1-ethyl-1,2,5,6-tetrahydropyridine;3-(1,2,5-Thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Hexylamino-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;ora pharmaceutically acceptable salt thereof.
 13. The method accordingto claim 1, wherein the compoundis:3-(3-Pentyl-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Heptyl-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(5-Hexenyl)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Octyl-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Isobutyl-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Cyclopropylmethyl-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Propyl-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;1,2,5,6-Tetrahydro-3-(3-(5-oxohexyl)-1,2,5-thiadiazol-4-yl)-1-methylpyridine;ora pharmaceutically acceptable salt thereof.
 14. The method according toclaim 1, wherein the compoundis:3-(3-Methylsulfonyl-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(4-Methylenecyclohexylmethyl)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;ora pharmaceutically acceptable salt thereof.
 15. The method accordingto claim 1, wherein the compoundis:3-(3-Amino-1,2,5-oxadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Acetylamino-1,2,5-oxadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Chloro-1,2,5-oxadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(1,2,5-Oxadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine; orapharmaceutically acceptable salt thereof.
 16. The method according toclaim 1, wherein the compoundis:3-(3-Hexyloxy-1,2,5-oxadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Butyloxy-1,2,5-oxadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(3-Hexynyloxy)-1,2,5-oxadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;ora pharmaceutically acceptable salt thereof.
 17. The method according toclaim 1, wherein the compoundis:3-(3-(3-Phenylpropylthio)-1,2,5-oxadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(2-Phenoxyethylthio)-1,2,5-oxadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Pentylthio-1,2,5-oxadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-Hexylthio-1,2,5-oxadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(4-Pentynylthio)-1,2,5-oxadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;ora pharmaceutically acceptable salt thereof.